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1.
  • Patinha, Daniela, et al. (författare)
  • Angiotensin II contributes to glomerular hyperfiltration in diabetic rats independently of adenosine type I receptors
  • 2013
  • Ingår i: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY. - : American Physiological Society. - 1931-857X .- 1522-1466 .- 0363-6127. ; 304:5, s. F614-F622
  • Tidskriftsartikel (refereegranskat)abstract
    • Increased angiotensin II (ANG II) or adenosine can potentiate each other in the regulation of renal hemodynamics and tubular function. Diabetes is characterized by hyperfiltration, yet the roles of ANG II and adenosine receptors for controlling baseline renal blood flow (RBF) or tubular Na+ handling in diabetes is presently unknown. Accordingly, the changes in their functions were investigated in control and 2-wk streptozotocin-diabetic rats after intrarenal infusion of the ANG II AT(1) receptor antagonist candesartan, the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or their combination. Compared with controls, the baseline blood pressure, RBF, and renal vascular resistance (RVR) were similar in diabetics, whereas the glomerular filtration rate (GFR) and filtration fraction (FF) were increased. Candesartan, DPCPX, or the combination increased RBF and decreased RVR similarly in all groups. In controls, the GFR was increased by DPCPX, but in diabetics, it was decreased by candesartan. The FF was decreased by candesartan and DPCPX, independently. DPCPX caused the most pronounced increase in fractional Na+ excretion in both controls and diabetics, whereas candesartan or the combination only affected fractional Li+ excretion in diabetics. These results suggest that RBF, via a unifying mechanism, and tubular function are under strict tonic control of both ANG II and adenosine in both control and diabetic kidneys. Furthermore, increased vascular AT(1) receptor activity is a contribution to diabetes-induced hyperfiltration independent of any effect of adenosine A(1) receptors.
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2.
  • Andersson, Maria, 1976, et al. (författare)
  • Mild renal ischemia-reperfusion reduces charge and size selectivity of the glomerular barrier
  • 2007
  • Ingår i: American Journal of Physiology Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1931-857X .- 1522-1466. ; 292:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Despite recent discoveries of molecules in podocytes, the mechanisms behind most conditions of proteinuria are still poorly understood. To understand more about this delicate barrier, we studied the functional and morphological effects of mild (15 min) renal ischemia-reperfusion injury (IRI). Renal function was studied in rats in vivo, followed by a more detailed analysis of the glomerular barrier in cooled (8 degrees C) isolated perfused kidneys (cIPK). Renal blood flow was quickly restored, whereas the glomerular filtration rate remained halved 30 min after IRI. Tubular cell activity was intact as judged from the unaffected Cr-EDTA U/P concentration ratio. In vivo, the fractional clearance (theta) for albumin increased 16 times. In rats subjected to cIPK starting 30 min after in vivo IRI, theta(albumin) was 15 times and theta(Ficoll_36angstroms) 1.8 times higher than in control cIPKs. According to the heterogeneous charged fiber model, IRI reduced the fiber charge density to 38% of control (P < 0.01, n = 7). Morphometric analysis with electron microscopy did not reveal any changes in the podocytes or the glomerular basement membrane (GBM) after IRI, suggesting more subtle changes of the GBM and/or the endothelial glycocalyx. We conclude that mild renal IRI induces formation of reactive oxygen species, massive proteinuria, and loss of charged fibers with no apparent change in morphology. These novel findings stress the importance of other components of the barrier, such as proteoglycans produced by the glomerular cells, and provide a tentative explanation for the mechanisms behind proteinuria in glomerulonephritis, for example.
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3.
  • Asgeirsson, Daniel, et al. (författare)
  • Increased glomerular permeability to negatively charged Ficoll relative to neutral Ficoll in rats.
  • 2006
  • Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 291:5, s. 1083-1089
  • Tidskriftsartikel (refereegranskat)abstract
    • It is established that the glomerular filter sieves macromolecules based on their size, shape, and charge. Anionic proteins are thus retarded compared with their neutral or cationic counterparts. However, recent studies have indicated that charge effects are small, or even "anomalous," for polysaccharides. We therefore investigated the impact of charge on the glomerular permeability to polysaccharides by comparing sieving coefficients ({theta}; primary urine-to-plasma concentration ratio) for negatively charged, carboxymethylated (CM) FITC-Ficoll and FITC-dextran with their neutral counterparts. For these probes, {theta} were determined in anesthetized Wistar rats [269 ± 2.7 g (±SE; n = 36)], whose ureters were cannulated for urine sampling. The glomerular filtration rate was assessed using FITC-inulin. Polysaccharides were constantly infused, and after equilibration, urine was collected and a midpoint plasma sample was taken. Size and concentration determinations of the FITC-labeled polysaccharides were achieved by size-exclusion HPLC (HPSEC). For CM-Ficoll, {theta} was significantly increased (32 times at 55 Å) compared with that of uncharged Ficoll. A small increase in {theta} for CM-dextran compared with neutral dextran was also observed (1.8 times at 55 Å). In conclusion, negatively charged Ficoll relative to neutral Ficoll was found to be markedly hyperpermeable across the glomerular filter. Furthermore, negatively charged Ficoll was observed to be larger on HPSEC compared with its neutral counterpart of the same molecular weight. It is proposed that the introduction of negative charges in the "dendrimeric," cross-linked Ficoll molecule may alter its configuration, so as to make it more extended, and conceivably, more flexible, thereby increasing its glomerular permeability. charge barrier; capillary permeability; macromolecules; fractional clearance; reflection coefficients IT IS GENERALLY ACCEPTED THAT the glomerular filter discriminates among macromolecules based on their size, shape, and net charge (6, 8). With respect to charge, the permeability of anionic dextran sulfate was found to be reduced and that of cationic, diethylaminoethyl (DEAE) dextran to be increased compared with that of neutral dextran (6). However, more recent studies have indicated that sulfated dextran may be processed in the kidney (28) and desulfated during its renal passage (10), and furthermore, that it may bind to plasma proteins (17), and to membrane phospholipids (25), causing an artifactual reduction in the sieving coefficients ({theta}; i.e., the primary urine-to-plasma concentration ratios) of dextran sulfate. In addition, isolated glomerular basement membranes (GBM) have generally failed to show charge selectivity when probed with neutral and negatively charged Ficoll (7) or native (anionic) or cationized albumin (4). In line with these findings, Schaeffer et al. (26) were unable to find (in rats in vivo) any difference between glomerular {theta} to carboxymethylated (non-sulfated) dextran or to hydroxymethyl starch (HES), both negatively charged, and their neutral counterparts. Furthermore, the HES molecules showed lower {theta} for any given Stokes-Einstein (SE) radius (cf. Ficoll) than did dextran. It was concluded that the glomerular filtration barrier restricts the transport of polysaccharide macromolecules as a function of size and configuration whereas the presence or absence of negative charge does not play any role. Further supporting these results, Guimarães et al. (18) did not find a decrease in glomerular permeability to negatively charged, carboxymethylated (CM) Ficoll compared with uncharged Ficoll, confirming a previous observation by Greive et al. (16). Instead, they found a markedly increased glomerular permeability to CM-Ficoll. In contrast to the apparent inability of the glomerular filter to discriminate between polysaccharides of different charge, there is ample evidence that, indeed, the glomerular filter selects globular proteins based on their charge. Thus anionic proteins are retarded compared with neutral and cationic proteins, as extensively reviewed by Comper and Glasgow (9) and Venturoli and Rippe (29). The reason the glomerular capillary wall exhibits low discrimination ability with respect to differently charged polysaccharides, while being able to separate proteins of different molecular charge, is obscure. However, one clue to this enigma could be the fact that carbohydrates exhibit an extended molecular configuration, with a larger SE radius, compared with that for globular proteins, for any given molecular mass (19, 29). Such an extended configuration, conceivably, generates a more flexible (compressible) structure and hence increases the molecule's permeability through the glomerular filtration barrier (29). Charge modification of a polysaccharide may lead to a further increase in molecular extension, favoring an increased flexibility and, thereby, an increased solute permeability. Could the process of charge modification of the highly cross linked and "ellipsoid" molecules of Ficoll (19) lead to conformational alterations, with increased molecular extension, increasing their permeability compared with their uncharged counterparts? If so, would the linear, "random coil," structure of dextran make it less affected by conformational changes, and thereby less hyperpermeable, when negatively charged? The present study was performed to test this hypothesis by comparing glomerular sieving coefficients to negatively charged, CM-Ficoll and -dextran vs. their uncharged molecular equivalents.
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4.
  • Axelsson, Josefin, et al. (författare)
  • Acute hyperglycemia induces rapid, reversible increases of glomerular permeability in non-diabetic rats.
  • 2010
  • Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 298:6, s. 1306-1312
  • Tidskriftsartikel (refereegranskat)abstract
    • This study was performed to investigate the impact of acute hyperglycemia (HG) on the permeability of the normal glomerular filtration barrier in vivo. In anaesthetized Wistar rats (250-280g), the left ureter was catheterized for urine collection, while simultaneously blood access was achieved. Rats received an intravenous (i.v.) infusion of either 1) hypertonic glucose to maintain blood glucose at 20-25 mM (G; n=8); 2) hypertonic glucose as in 1) and a Rho-A-kinase inhibitor (Y-27632; Rho-G; n=8); 3) 20% mannitol (MANN; n=7), or 4) hypertonic (12%) NaCl to maintain plasma crystalloid osmotic pressure (picry) at ~320-325 mOsm/l (NaCl; n=8); 5) physiologic saline (SHAM; n=8). Fluorescein isothiocyanate (FITC)-Ficoll 70/400 was infused i.v. for at least 20 min before terminating the experiments, and plasma and urine collected to determine the glomerular sieving coefficients () for polydisperse Ficoll (mol. radius 15-80A) by high performance size exclusion chromatography. In G there was a marked increase in for Ficoll55-80A at 20 min, which was completely reversible within 60 min and abrogated by a Rho-kinase (ROCK) inhibitor, while glomerular permeability remained unchanged in MANN and NaCl. In conclusion, acute HG caused rapid, reversible increases in for large Ficolls, not related to the concomitant hyperosmolarity, but sensitive to ROCK inhibition. The changes observed were consistent with the formation of an increased number of large pores in the glomerular filter. The sensitivity of the permeability changes to ROCK inhibition strongly indicates that the cytoskeleton of the cells in the glomerular barrier be involved in these alterations. Key words: microalbuminuria, Rho-A-kinase, podocytes, endothelium.
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5.
  • Axelsson, Josefin, et al. (författare)
  • Effects of early endotoxemia and dextran-induced anaphylaxis on the size-selectivity of the glomerular filtration barrier in rats.
  • 2009
  • Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 296:2, s. 242-248
  • Tidskriftsartikel (refereegranskat)abstract
    • This study was performed to investigate the glomerular permeability alterations responsible for the microalbuminuria occurring in endotoxemia and during anaphylactic shock. In anaesthetized Wistar rats, the left ureter was catheterized for urine collection, while simultaneously, blood access was achieved. Endotoxemia was induced by Lipopolysaccharide (LPS) from E. Coli, and glomerular permeability assessed at 60, 90 (ENDO-(60)/90; n=7) and 120 min (ENDO-120; n=7). Anaphylaxis was induced by a bolus dose of Dextran-70, and glomerular permeability assessed at 5 min (ANA-5; n=8) and 40 min (ANA-40; n=9). Sham animals, were followed for either 5 or 120 min. The glomerular sieving coefficients () to FITC-Ficoll (70/400) were determined from plasma and urine samples and assessed using size-exclusion chromatography (HPLC). 2 h after start of the LPS infusion, but not at 60 or 90 min, for Ficoll70A had increased markedly (from 2.91 x 10(-5) +/- 6.33 x 10(-6) to 7.78 x 10(-5) +/- 6.21 x 10(-6) (P<0.001)). In anaphylaxis there was a large increase in for Ficolls >60 A in mol. radius already at 5 min, but the glomerular permeability was completely restored at 40 min. In conclusion, there was a transient, immediate increment of glomerular permeability in dextran-induced anaphylaxis, which was completely reversible within 40 min. By contrast, endotoxemia caused an increase in glomerular permeability that was manifest first after 2 h. In both cases to large Ficoll molecules were markedly increased, reflecting an increase in the number of large pores in the glomerular filter. Key words: capillary permeability, Ficoll, sieving coefficient, albumin.
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6.
  • Axelsson, Josefin, et al. (författare)
  • Loss of size-selectivity of the glomerular filtration barrier in rats following laparotomy and muscle trauma.
  • 2009
  • Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 297, s. 577-582
  • Tidskriftsartikel (refereegranskat)abstract
    • Post-traumatic microalbuminuria may be caused by either charge- or size-selective alterations in the glomerular filtration barrier, or both, and/or to a reduction in proximal tubular protein reabsorption (PTR). This study was performed to elucidate the pathophysiology of the increases in glomerular permeability occurring in rats exposed to laparotomy or to laparotomy and muscle trauma. In anaesthetized Wistar rats (250-280 g), the left ureter was catheterized for urine collection, while simultaneously blood access was achieved. Rats were exposed to trauma by laparotomy (L) (n=8), or by a combination of L and muscle trauma (MT), induced by topical blunt injury of the abdominal muscles bilaterally. After L muscles were crushed using a hemostatic forceps at either 2x2 sites ("small" MT; n=9), or at 2x5 sites ("large" MT; n=9). Sham groups (n=16), not exposed to laparotomy, were used as controls. The glomerular sieving coefficients () to polydisperse, fluorescein isothiocyanate (FITC)-Ficoll-70/400 (mol.radius 13-80A) were determined at 5 or 60 min after L and (L + MT), respectively, from plasma and urine samples, and analyzed by high performance size-exclusion chromatography (HPSEC). A tissue uptake technique was used to assess for (125)I-serum albumin. L, with or without MT, increased for Ficoll55-80A and albumin rapidly and markedly. -Ficoll70A thus increased approximately threefold, and for albumin significantly, for all trauma groups. According to the "two-pore model" of glomerular permeability these changes reflect an increase in the number of large pores in the glomerular filter without any primary changes in the charge-selective properties of the filter. Key words: microalbuminuria, glomerular sieving coefficients, albumin, Ficoll.
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7.
  • Axelsson, Josefin, et al. (författare)
  • mTOR inhibition with temsirolimus causes acute increases in glomerular permeability, but inhibits the dynamic permeability actions of puromycin aminonucleoside.
  • 2015
  • Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 308:10, s. 1056-1064
  • Tidskriftsartikel (refereegranskat)abstract
    • Inhibitors of the mammalian target of rapamycin (mTORi) can produce de novo proteinuria in kidney transplant patients. On the other hand, mTORi has been shown to suppress disease progression in several animal models of kidney disease. In the present study we investigated whether glomerular permeability can be acutely altered by the mTORi, temsirolimus, and whether mTORi can affect acute purumycin aminonucleoside (PAN) or angiotensin II (AngII) induced glomerular hyperpermeability. In anaesthetized Wistar rats, the left ureter was cannulated for urine collection, while simultaneously, blood access was achieved. Temsirolimus was administered as a single dose i.v. 30 min before the start of the experiments in animals infused with PAN or AngII or in non-exposed animals. Polydispersed FITC-Ficoll-70/400 (mol.radius 10-80Å) and (51)Cr-EDTA infusion was given during the whole experiment. Measurements of Ficoll in plasma and urine were performed sequentially before the temsirolimus injection (baseline) and at 5, 15, 30, 60 and 120 min after the start of the experiments. Urine and plasma samples were analyzed by high performance size exclusion chromatography (HPSEC) to assess glomerular sieving coefficients (θ) for Ficoll10-80Å. Temsirolimus per se increased baseline glomerular permeability to Ficoll50-80Å 45 min after its administration, a ROS dependent phenomenon. PAN caused a rapid and reversible increase in glomerular permeability, peaking at 5 min, and again at 60-120 min, which could be blocked by the ROS scavenger, tempol. mTORi abrogated the second permeability peak induced by PAN. However, it had no effect on the immediate AngII or PAN induced increases in glomerular permeability.
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8.
  • Axelsson, Josefin, et al. (författare)
  • Rapid, dynamic changes in glomerular permeability to macromolecules during systemic Angiotensin II (AngII) infusion in rats.
  • 2012
  • Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 303:6, s. 790-799
  • Tidskriftsartikel (refereegranskat)abstract
    • The actions of systemic angiotensin II (AngII) infusions on glomerular permeability were investigated in vivo. In anaesthetized Wistar rats (250-280g) the left ureter was cannulated for urine collection, while simultaneously blood access was achieved. Rats were continuously infused i.v. with either of four doses of AngII (16 ng/kg/min (Lo-AngII; n=7), 230 ng/kg/min (Lo-Int-AngII; n=8), 910 ng/kg/min (Hi-Int-AngII; n=7), or 1.82 μg/kg/min (Hi-AngII; n=8)), or with the calcium channel blocker, nimodipine, together with the Hi-Int-AngII dose (n=6), respectively, and with polydisperse fluorescein isothiocyanate (FITC)-Ficoll-70/400 (mol.radius 10-80Å) and (51)Cr-EDTA. Plasma and urine samples were taken at 5, 15, 30, 60 and 120 min and analyzed by high performance size exclusion chromatography (HPSEC) for determination of glomerular sieving coefficients (θ) to Ficoll. Mean arterial pressure (MAP) and glomerular filtration rate (GFR) were also assessed. In AngII groups there was a rapid, marked increase in glomerular permeability (θ) to Ficoll molecules >34Å, which was completely abrogated by the AngII-blocker, candesartan. The permeability increase was reversible within 15-60 min, but some increases remained even after 60 min. For the highest AngII doses given GFR decreased transiently, concomitant with marked increases in MAP. Nimodipine blocked the hemodynamic AngII actions, whereas the glomerular permeability response remained unchanged. According to a two-pore model and a log-normal distributed pore model the AngII induced increases in glomerular permeability are compatible with an increased number of "large pores" in the glomerular filter, and, to some extent, an increase in the dispersity of the small pore radius.
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9.
  • Axelsson, Josefin, et al. (författare)
  • Reduced diffusion of charge-modified, conformationally intact anionic Ficoll relative to neutral Ficoll across the rat glomerular filtration barrier in vivo
  • 2011
  • Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 301:4, s. 708-712
  • Tidskriftsartikel (refereegranskat)abstract
    • Axelsson J, Sverrisson K, Rippe A, Fissell W, Rippe B. Reduced diffusion of charge-modified, conformationally intact anionic Ficoll relative to neutral Ficoll across the rat glomerular filtration barrier in vivo. Am J Physiol Renal Physiol 301: F708-F712, 2011. First published July 20, 2011; doi:10.1152/ajprenal.00183.2011.-The glomerular filtration barrier (GFB) is commonly conceived as a negatively charged sieve to proteins. Recent studies, however, indicate that glomerular charge effects are small for anionic, carboxymethylated (CM) dextran vs. neutral dextran. Furthermore, two studies assessing the glomerular sieving coefficients (theta) for negative CM-Ficoll vs. native Ficoll have demonstrated an increased glomerular permeability for CM-Ficoll (Asgeirsson D, Venturoli D, Rippe B, Rippe C. Am J Physiol Renal Physiol 291: F1083-F1089, 2006; Guimaraes M, Nikolovski J, Pratt L, Greive K, Comper W. Am Physiol Renal Physiol 285: F1118-F1124, 2003.). The CM-Ficoll used, however, showed a larger Stokes-Einstein radius (a(e)) than neutral Ficoll, and it was proposed that the introduction of negative charges in the Ficoll molecule had made it more flexible and permeable. Recently, a negative FITC-labeled CM-Ficoll (CMI-Ficoll) was produced with a conformation identical to that of neutral FITC-Ficoll. Using these probes, we determined their theta:s in anesthetized Wistar rats (259 +/- 2.5 g). After blood access had been achieved, the left ureter was cannulated for urine sampling. Either polysaccharide was infused (iv) together with a filtration marker, and urine and plasma were collected. Assessment of theta FITC-Ficoll was achieved by high-performance size-exclusion chromatography (HPSEC). CMI-Ficoll and native Ficoll had identical elugrams on the HPSEC. Diffusion of anionic Ficoll was significantly reduced compared with that of neutral Ficoll across the GFB for molecules of a(e) similar to 20-35 angstrom, while there were no charge effects for Ficoll of a(e) similar to 35-80 angstrom. The data are consistent with a charge effect present in "small pores," but not in "large pores," of the GFB and mimicked those obtained for anionic membranes in vitro for the same probes.
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10.
  • Axelsson, Josefin, et al. (författare)
  • Scavengers of reactive oxygen species, paracalcitol, RhoA and Rac-1 inhibitors and tacrolimus inhibit angiotensin II induced actions on glomerular permeability.
  • 2013
  • Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 305:3, s. 237-243
  • Tidskriftsartikel (refereegranskat)abstract
    • Systemic infusions of angiotensin II (AngII) rapidly induce large, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor(s), AngII generates reactive oxygen species (ROS) and produces Ca(2+) influx into cells, leading to activation of a plethora of signaling cascades, including e.g. calcineurin, and small GTPases, such as Rac-1 and RhoA. In the present study we sought to interact with some of these cascades in order to test potential novel antiproteinuric agents. In anaesthetized Wistar rats the left urether was cannulated for urine collection, and blood access was achieved. Rats were infused with AngII (16 ng/kg/min) alone, or together with the ROS scavengers, TEMPOL or dimethylthiourea (DMTU), or the D-vitamin analog, paracalcitol, the RhoA-kinase inhibitor, Y-27632, the Rac-1 inhibitor, NSC-23766, or the calcineurin inhibitor, tacrolimus. FITC-Ficoll-70/400 (mol.radius 10-80Å) and (51)Cr-EDTA were infused throughout the experiment. Plasma and urine samples were taken during baseline and at 5 and 15 min after the start of the infusions and analyzed by high performance size exclusion chromatography (HPSEC) for determination of glomerular sieving coefficients (θ) for Ficoll10-80Å. AngII infusion into rats caused marked increases in glomerular permeability to large Ficoll molecules (Ficoll50-80Å), which were abrogated by the ROS scavenger TEMPOL and partly by DMTU. Paracalcitol, RhoA and Rac-1 inhibition, and, to some extent, tacrolimus, but not prostacyclin, could also inhibit the glomerular permeability actions of AngII. Our data suggest that cellular ROS generation and active Ca(2+) signaling are involved in AngII induced increases in glomerular permeability.
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11.
  • Axelsson, Josefin, et al. (författare)
  • Transient and sustained increases in glomerular permeability following ANP infusion in rats.
  • 2011
  • Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 300, s. 24-30
  • Tidskriftsartikel (refereegranskat)abstract
    • The present study was performed to investigate the effects of systemic atrial natriuretic peptide (ANP) infusion on the glomerular permeability to macromolecules in rats. In anaesthetized Wistar rats (250-280g) the left urether was cannulated for urine collection while simultaneously blood access was achieved. Rats were continuously infused i.v. with ANP, 30 ng/min/kg (Lo-ANP; n=8) or 800 ng/min/kg (Hi-ANP; n=10) or 0.9% NaCl (SHAM; n=16), respectively, and with polydisperse fluorescein isothiocyanate (FITC)-Ficoll-70/400 (mol.radius 13-90Å) and (51)Cr-EDTA for 2 h. Plasma and urine samples were taken at 5, 15, 30, 60 and 120 min of ANP infusion, and analyzed by high performance size exclusion chromatography (HPLC) for determination of glomerular sieving coefficients () for Ficoll. GFR was also assessed ((51)Cr-EDTA). In Hi-ANP there was a rapid (within 5 min), but bimodal, increase in glomerular permeability. to high MW Ficoll thus reached a maximum at 15 min, after which returned to near control at 30 min, to again increase moderately at 60 and 120 min. In Lo-ANP there was also a rapid, reversible increase in glomerular , returning to near control at 30 min, followed by just a tendency of a sustained increase in permeability, but with a significant increase in "large pore" radius. In conclusion, in Hi-ANP there was a rapid increase in glomerular permeability, with an early, partly reversible permeability peak, followed by a (moderate) sustained increase in permeability. In Lo-ANP animals, only the initial permeability peak was evident. In both Lo-ANP and Hi-ANP the glomerular sieving pattern observed was found to mainly reflect an increase in the number and radius of "large pores" in the glomerular filter.
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12.
  • Bertram, Michael (författare)
  • Podocyte endowment and the impact of adult body size on kidney health
  • 2021
  • Ingår i: American journal of physiology - renal physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 321, s. F322-F334
  • Tidskriftsartikel (refereegranskat)abstract
    • Low birth weight is a risk factor for chronic kidney disease, whereas adult podocyte depletion is a key event in the pathogenesis of glomerulosclerosis. However, whether low birth weight due to poor maternal nutrition is associated with low podocyte endowment and glomerulosclerosis in later life is not known. Female Sprague-Dawley rats were fed a normal-protein diet (NPD; 20%) or low-protein diet (LPD; 8%), to induce low birth weight, from 3 wk before mating until postnatal day 21 (PN21), when kidneys from some male offspring were taken for quantitation of podocyte number and density in whole glomeruli using immunolabeling, tissue clearing, and confocal microscopy. The remaining offspring were fed a normal- or high-fat diet until 6 mo to induce catchup growth and excessive weight gain, respectively. At PN21, podocyte number per glomerulus was 15% lower in low birth weight (LPD) than normal birth weight (NPD) offspring, with this deficit greater in outer glomeruli. Surprisingly, podocyte number in LPD offspring increased in outer glomeruli between PN21 and 6 mo, although an overall 9% podocyte deficit persisted. Postnatal fat feeding to LPD offspring did not alter podometric indexes or result in glomerular pathology at 6 mo, whereas fat feeding in NPD offspring was associated with far greater body and fat mass as well as podocyte loss, reduced podocyte density, albuminuria, and glomerulosclerosis. This is the first report that maternal diet can influence podocyte endowment. Our findings provide new insights into the impact of low birth weight, podocyte endowment, and postnatal weight on podometrics and kidney health in adulthood.NEW & NOTEWORTHY The present study shows, for the first time, that low birth weight as a result of maternal nutrition is associated with low podocyte endowment. However, a mild podocyte deficit at birth did not result in glomerular pathology in adulthood. In contrast, postnatal podocyte loss in combination with excessive body weight led to albuminuria and glomerulosclerosis. Taken together, these findings provide new insights into the associations between birth weight, podocyte indexes, postnatal weight, and glomerular pathology.
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13.
  • Björnson Granqvist, Anna, 1974, et al. (författare)
  • Impaired glomerular and tubular antioxidative defense mechanisms in nephrotic syndrome.
  • 2010
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 299:4
  • Tidskriftsartikel (refereegranskat)abstract
    • The molecular mechanisms behind acquired nephrotic syndrome (NS) are still largely unknown. One possible explanation for the development of proteinuria is oxidative damage to the glomerular cells. Our hypothesis was that the oxidative defense is weakened in NS, and we focused on measurements of the oxidative-antioxidative status in the glomerular and tubular parts of the nephron. Gene expression was analyzed in renal biopsies from patients with NS. In addition, to compare the acute and chronic phases of the disease, we studied puromycin-treated rats. In the biopsy material, the expression of enzymes involved in the antioxidative defense was higher in the tubulointerstitial compartment than in the glomerular cells. Real-time PCR analysis revealed a decreased glomerular expression in nephrotic kidneys for the antioxidant enzymes catalase and glutathione peroxidase-3, and -4. The tubular gene expression was downregulated for catalase, glutathione peroxidase-3, and thioredoxin reductase-1 and -2. The altered gene expression was accompanied by increased lipid peroxidation in urine. In rats, serum concentrations of ascorbyl-free radicals, measured with electron spin resonance, were elevated in the acute phase of the disease, suggesting increased oxidative stress in the circulation. In addition, we saw an increase in the plasma antioxidant capacity combined with a decreased oxidation of proteins in sera from nephrotic rats, but not from humans. In conclusion, there is a marked downregulation of several antioxidative enzymes in nephrotic kidneys, especially in glomerular structures. Our data suggest that oxidative damage to glomerular cells may contribute significantly to the course and prognosis of nephrotic syndrome.
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14.
  • Boubred, F, et al. (författare)
  • Early postnatal overfeeding induces early chronic renal dysfunction in adult male rats
  • 2009
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 297:4, s. F943-F951
  • Tidskriftsartikel (refereegranskat)abstract
    • Low birth weight is associated with an increased risk of hypertension and renal dysfunction at adulthood. Such an association has been shown to involve a reduction of nephron endowment and to be enhanced by accelerated postnatal growth in humans. However, while low-birth-weight infants often undergo catch-up growth, little is known about the long-term vascular and renal effects of accelerated postnatal growth. We surimposed early postnatal overfeeding (OF; reduction of litter size during the suckling period) to appropriate-birth-weight (NBW+OF) and intrauterine growth restriction (IUGR; IUGR+OF) pups, obtained after a maternal gestational low-protein diet. Blood pressure (systolic blood pressure; SBP) and renal function (glomerular filtration rate; GFR) were measured in young and aging offspring. Glomerulosclerosis and nephron number were determined in aging offspring (22 mo). Nephron number was reduced in both IUGR and IUGR+OF male offspring (by 24 and 26%). GFR was reduced by 40% in 12-mo-old IUGR+OF male offspring, and both NBW+OF and IUGR+OF aging male offspring had sustained hypertension (+25 mmHg) and glomerulosclerosis, while SBP and renal function were unaffected in IUGR aging offspring. Female offspring were unaffected. In conclusion, in this experimental model, early postnatal OF in the neonatal period has major long-lasting effects. Such effects are gender dependent. Reduced nephron number alone, associated with IUGR, may not be sufficient to induce long-lasting physiological alterations, and early postnatal OF acts as a “second hit.” Early postnatal OF is a suitable model with which to study the long-term effects of postnatal growth in the pathogenesis of vascular disorders and renal disease.
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15.
  • Boubred, F, et al. (författare)
  • Effects of early postnatal hypernutrition on nephron number and long-term renal function and structure in rats
  • 2007
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 293:6, s. F1944-F1949
  • Tidskriftsartikel (refereegranskat)abstract
    • Various antenatal events impair nephrogenesis in humans as well as in several animal models. The consecutive low nephron endowment may contribute to an increased risk for cardiovascular and renal diseases in adulthood. However, little knowledge is available on the influence of the postnatal environment, especially nutrition, on nephrogenesis. Moreover, the consequences of early postnatal nutrition in late adulthood are not clear. We used a model of early postnatal overfeeding (OF) induced by reduction of litter size (3 pups/litter) in rats. Systolic blood pressure (SBP; plethysmography), glomerular filtration rate (clearance of creatinine), glomerular number and volume, and glomerulosclerosis were evaluated in 22-mo-old aging offspring. Early postnatal OF was associated with increased weight gain during the suckling period (+40%, P < 0.01) and a 20% increase in glomerular number ( P < 0.05). However, an increase in SBP at 12 mo by an average of 18 mmHg and an increase in proteinuria (2.6-fold) and glomerulosclerosis at 22 mo of age were observed in OF male offspring compared with controls. In conclusion, early postnatal OF in the rat enhances postnatal nephrogenesis, but elevated blood pressure and glomerulosclerosis are still observed in male adults. Factors other than glomerular number reduction are likely to contribute to the arterial hypertension induced by early postnatal OF.
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16.
  • Brown, Russell D., et al. (författare)
  • Tubuloglomerular feedback response in the prenatal and postnatal ovine kidney
  • 2011
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 300:6, s. F1368-F1374
  • Tidskriftsartikel (refereegranskat)abstract
    • Brown RD, Turner AJ, Carlstrom M, Persson AE, Gibson KJ. Tubuloglomerular feedback response in the prenatal and postnatal ovine kidney. Am J Physiol Renal Physiol 300: F1368-F1374, 2011. First published March 30, 2011; doi:10.1152/ajprenal. 00019.2011.-The tubuloglomerular feedback mechanism (TGF) plays an important role in regulating single-nephron glomerular filtration rate (GFR) by coupling distal tubular flow to arteriolar tone. It is not known whether TGF is active in the developing kidney or whether it can regulate renal vascular tone and thus GFR during intrauterine life. TGF characteristics were examined in late-gestation ovine fetuses and lambs under normovolemic and volume-expanded (VE) conditions. Lambs and pregnant ewes were anesthetized and the fetuses were delivered via a caesarean incision into a heated water bath, with the umbilical cord intact. Under normovolemic conditions, mean arterial pressure of the fetuses was lower than lambs (51 +/- 1 vs. 64 +/- 3 mmHg). The maximum TGF response (Delta P(SFmax)) was found to be lower in fetuses than lambs when tubular perfusion was increased from 0 to 40 nl/min (5.4 +/- 0.7 vs. 10.6 +/- 0.4 mmHg). Furthermore, the flow rate eliciting half-maximal response [turning point (TP)] was 15.7 +/- 0.9 nl/min in fetuses compared with 19.3 +/- 1.0 nl/min in lambs, indicating a greater TGF sensitivity of the prenatal kidney. VE decreased Delta P(SFmax) (4.2 +/- 0.4 mmHg) and increased TP to 23.7 +/- 1.3 nl/min in lambs. In fetuses, VE increased stop-flow pressure from 26.6 +/- 1.5 to 30.3 +/- 0.8 mmHg, and reset TGF sensitivity so that TP increased to 21.3 +/- 0.7 nl/min, but it had no effect on Delta P(SFmax). This study provides direct evidence that the TGF mechanism is active during fetal life and responds to physiological stimuli. Moreover, reductions in TGF sensitivity may contribute to the increase in GFR at birth.
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17.
  • Bustamante, M, et al. (författare)
  • Insulin potentiates AVP-induced AQP2 expression in cultured renal collecting duct principal cells
  • 2005
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 288:2, s. F334-F344
  • Tidskriftsartikel (refereegranskat)abstract
    • In the renal collecting duct (CD), water reabsorption depends on the presence of aquaporin-2 (AQP2) in the apical membrane of principal cells. AQP2 expression and subcellular repartition are under the control of AVP. Some pieces of experimental evidence indicate that additional hormonal factors, including insulin, may also control AQP2 expression and thereby CD water permeability. We have previously shown that AVP induces endogenous AQP2 expression in cultured mouse mpkCCDcl4CD principal cells ( 23 ). In the present study, we investigated the effect of insulin on AQP2 expression in mpkCCDcl4cells. Addition of insulin to the basal medium of cells grown on filters slightly increased AQP2 mRNA and protein expression, whereas insulin potentiated the effect of AVP. The potentiation of AVP-induced AQP2 expression by insulin was abolished by actinomycin D, a transcriptional inhibitor. Analysis of AQP2 protein expression under conditions of AVP washout and/or in the presence of chloroquine, a lysosomal degradation inhibitor, revealed that insulin did not significantly alter AQP2 protein degradation. Inhibition of ERK, p38 kinase, and phosphatidylinositol 3′-kinase (PI 3-kinase) activities prevented the insulin-induced stimulation of AQP2 expression, whereas inhibition of PKC has no effect. Taken together, our results indicate that insulin increased AQP2 protein expression mostly through increased AQP2 mRNA levels in cultured mpkCCDcl4cells. This effect most likely relies on increased AQP2 gene transcription in response to MAPK and PI 3-kinase activation.
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18.
  • Carlstrom, M, et al. (författare)
  • Adenosine A(2) receptors modulate tubuloglomerular feedback
  • 2010
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 299:2, s. F412-F417
  • Tidskriftsartikel (refereegranskat)abstract
    • Adenosine can mediate the tubuloglomerular (TGF) response via activation of A1 receptors on the afferent arteriole, but both adenosine A1 and A2 receptors can regulate preglomerular resistance. We tested the hypothesis that adenosine A2 receptors offset the effect of A1 receptors and modulate the TGF. Maximal TGF responses were measured in male Sprague-Dawley rats as changes in proximal stop-flow pressure (ΔPSF) in response to increased perfusion of the loop of Henle (0 to 40 nl/min) with artificial tubular fluid (ATF). The maximal TGF response was studied after 5 min of intratubular perfusion (10 nl/min) with ATF alone, or with ATF plus the A2A receptor antagonist (ZM-241385; 10−7 or 10−5 mol/l), A1 receptor antagonist (PSB-36; 10−8 mol/l), or with a combination of A1 (PSB-36; 10−8 mol/l) and A2A (ZM-241385; 10−7 mol/l) antagonists. The maximal TGF response (ΔPSF) with ATF alone was 11.7 ± 1.0 mmHg. Specific A2 inhibition (low dose) enhanced the maximal TGF response (15.7 ± 0.8 mmHg; P < 0.01), whereas a high dose (unspecific inhibition) attenuated the response (5.0 ± 0.4 mmHg; P < 0.001). A1 inhibition alone led to a paradoxical TGF response, with an increase in PSF of 3.1 ± 0.5 mmHg ( P < 0.05). Simultaneous application of A1 and A2 antagonists abolished the TGF response (ΔPSF: 0.4 ± 0.3 mmHg). In conclusion, adenosine A2 receptors modulate the TGF response by counteracting the effects of adenosine A1 receptors.
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19.
  • Carlstrom, M, et al. (författare)
  • Adenosine A2A receptor activation attenuates tubuloglomerular feedback responses by stimulation of endothelial nitric oxide synthase
  • 2011
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 300:2, s. F457-F464
  • Tidskriftsartikel (refereegranskat)abstract
    • Adenosine A2receptors have been suggested to modulate tubuloglomerular feedback (TGF) responses by counteracting adenosine A1receptor-mediated vasoconstriction, but the mechanisms are unclear. We tested the hypothesis that A2Areceptor activation blunts TGF by release of nitric oxide in the juxtaglomerular apparatus (JGA). Maximal TGF responses were measured in male Sprague-Dawley rats as changes in proximal stop-flow pressure (ΔPSF) in response to increased perfusion of the loop of Henle (0 to 40 nl/min) with artificial tubular fluid (ATF). The maximal TGF response was studied after 5 min intratubular perfusion (10 nl/min) with ATF or ATF + A2Areceptor agonist (CGS-21680; 10−7mol/l). The interaction with nitric oxide synthase (NOS) isoforms was tested by perfusion with a nonselective NOS inhibitor [ Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME); 10−3mol/l] or a selective neuronal NOS (nNOS) inhibitor [ Nω-propyl-l-arginine (l-NPA); 10−6mol/l] alone, and with the A2Aagonist. Blood pressure, urine flow, and PSFat 0 nl/min were similar among the groups. The maximal TGF response (ΔPSF) with ATF alone (12.3 ± 0.6 mmHg) was attenuated by selective A2Astimulation (9.5 ± 0.4 mmHg). l-NAME enhanced maximal TGF responses (18.9 ± 0.4 mmHg) significantly more than l-NPA (15.2 ± 0.7 mmHg). Stimulation of A2Areceptors did not influence maximal TGF response during nonselective NOS inhibition (19.0 ± 0.4) but attenuated responses during nNOS inhibition (10.3 ± 0.4 mmHg). In conclusion, adenosine A2Areceptor activation attenuated TGF responses by stimulation of endothelial NOS (eNOS), presumably in the afferent arteriole. Moreover, NO derived from both eNOS and nNOS in the JGA may blunt TGF responses.
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20.
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21.
  • Carlström, Mattias, et al. (författare)
  • Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals
  • 2008
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 294:2, s. 362-370
  • Tidskriftsartikel (refereegranskat)abstract
    • Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N-G- nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.
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22.
  • Charlton, Jennifer R., et al. (författare)
  • Beyond the tubule : pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease
  • 2020
  • Ingår i: American Journal of Physiology - Renal Physiology. - : AMER PHYSIOLOGICAL SOC. - 1931-857X .- 1522-1466. ; 319:6, s. F988-F999
  • Tidskriftsartikel (refereegranskat)abstract
    • Pathogenic variants in the LRP2 gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR) syndrome. Because of the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain, and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecularweight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FETC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and N-acetyl-11-n-glucosaminidase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease, and glomerular proteinuria early in life. Megalin-deficient mice had normal nephrogenesis, but they had 19% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction, as present in DB/FOAR syndrome, confers an increased risk of progression into chronic kidney disease.
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23.
  • Crambert, S, et al. (författare)
  • Prolactin and dopamine 1-like receptor interaction in renal proximal tubular cells
  • 2010
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 299:1, s. F49-F54
  • Tidskriftsartikel (refereegranskat)abstract
    • Prolactin is a natriuretic hormone and acts by inhibiting the activity of renal tubular Na+-K+-ATPase activity. These effects require an intact renal dopamine system. Here, we have studied by which mechanism prolactin and dopamine interact in Sprague-Dawley rat renal tissue. Na+-K+-ATPase activity was measured as ouabain-sensitive ATP hydrolysis in microdissected renal proximal tubular segments. Intracellular signaling pathways were studied by a variety of different techniques, including Western blotting using phosphospecific antibodies, immunoprecipitation, and biotinylation assays. We found that dopamine and prolactin regulated Na+-K+-ATPase activity via similar signaling pathways, including protein kinase A, protein kinase C, and phosphoinositide 3-kinase activation. The cross talk between prolactin and dopamine 1-like receptors was explained by a heterologous recruitment of dopamine 1-like receptors to the plasma membrane in renal proximal tubular cells. Prolactin had no effect on Na+-K+-ATPase activity in spontaneously hypertensive rats, a rat strain with a blunted response to dopamine. These results further emphasize the central role of the renal dopamine system in the interactive regulation of renal tubular salt balance.
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24.
  • Ding, Mei, et al. (författare)
  • Regulation of hypoxia-inducible factor 2-a is essential for integrity of the glomerular barrier
  • 2013
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 304:1, s. F120-F126
  • Tidskriftsartikel (refereegranskat)abstract
    • Deletion of the von Hippel-Lindau tumor suppressor (Vhl) gene from renal podocytes of mice (podVhl KO) leads to rapidly progressive glomerulonephritis (RPGN), a clinical syndrome characterized by rapid loss of renal function and crescents on renal biopsy. Genomic profiling of glomeruli isolated from podVhl knockout (KO) mice and from patients with RPGN identified a fingerprint of genes regulated by hypoxia-inducible factors (HIF), important substrates of the product of the VHL gene. Here, we show that stabilization of Hifs in podocytes is both required and sufficient for the glomerular phenotype observed in podVhl KO mice. Genetic deletion of the obligate dimerization partner Arnt/Hif1b that is essential for Hif transcriptional function rescues the phenotype. Conversely, stabilization of HIF2A alone in podocytes results in crescentic glomerular disease. Together, our results show that the Hif pathway and Hif2a in particular are key players in maintenance of the glomerular barrier.
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25.
  • Dolinina, Julia, et al. (författare)
  • Glomerular hyperpermeability after acute unilateral ureteral obstruction : Effects of Tempol, NOS, RhoA, and Rac-1 inhibition
  • 2018
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 315:3, s. 445-453
  • Tidskriftsartikel (refereegranskat)abstract
    • It is well known that proteinuria following urinary tract obstruction is mainly of a tubular nature. However, it is unknown whether there are also changes in glomerular permeability. In this study, we compared glomerular sieving coefficients (θ) of polydisperse fluorescein isothiocyanate (FITC)-Ficoll 70/400 following a 120-or 180-min unilateral ureteral obstruction (UUO) in anesthetized Sprague-Dawley rats. Samples were collected from the obstructed kidney at 5, 15, and 30 min postrelease and analyzed by means of high-pressure size-exclusion chromatography. After 120-min UUO, mean θ for Ficoll70Å was increased (P < 0.01) from 2.2 ± 0.5 × 10−5 (baseline) to 10.6 ± 10 × 10−5 15 min postrelease (highest value). After 180-min UUO, mean θ for Ficoll70Å was further increased (P < 0.001) from 1.4 ± 0.5 × 10−5 (baseline) to 40 ± 10 × 10−5 at 5 min postrelease (highest value). Administration of a reactive oxygen species (ROS) scavenger (Tempol; 1 mg·kg−1·min−1) partly abrogated the permeability effects following 120-min UUO but not after 180 min. Moreover, administration of the RhoA kinase inhibitor Y-27632, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, or Rac-1 inhibition did not ameliorate glomerular hyperpermeability following 180-min UUO. We show, for the first time, that acute UUO results in marked elevations in glomerular permeability. In addition, our data suggest a time-dependent pathophysiology of UUO-induced hyperpermeability, where reactive oxygen species generation may play an important role in the early stages.
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26.
  • Dolinina, Julia, et al. (författare)
  • Nitric oxide synthase inhibition causes acute increases in glomerular permeability in vivo, dependent upon reactive oxygen species
  • 2016
  • Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 311:5, s. 984-990
  • Tidskriftsartikel (refereegranskat)abstract
    • There is increasing evidence that the permeability of the glomerular filtration barrier (GFB) is partly regulated by a balance between the bioavailability of nitric oxide (NO) and that of reactive oxygen species (ROS). It has been postulated that normal or moderately elevated NO levels protect the GFB from permeability increases, whereas ROS, through reducing the bioavailability of NO, have the opposite effect. We tested the tentative antagonism between NO and ROS on glomerular permeability in anaesthetized Wistar rats, in which the left ureter was cannulated for urine collection while simultaneously blood access was achieved. Rats were systemically infused with eitherL-NAME orL-NAME together with the superoxide scavenger Tempol, or together withL-arginine or the NO-donor DEA-NONOate, or the cGMP agonist 8-bromo-cGMP. To measure glomerular sieving coefficients (theta, θ) to Ficoll, rats were infused with FITC-Ficoll 70/400 (mol/radius 10-80 Å). Plasma and urine samples were analyzed by high-performance size-exclusion chromatography (HPSEC) for determination of θ for Ficoll repeatedly during up to 2 h.L-NAME increased θ for Ficoll70Å from 2.27 ± 1.30 ˟ 10-5 to 8.46 ± 2.06 ˟ 10-5 (n = 6, P < 0.001) in 15 min. Tempol abrogated these increases in glomerular permeability and an inhibition was also observed withL-arginine and with 8-bromo-cGMP. In conclusion, acute NO synthase inhibition in vivo byL-NAME caused rapid increases in glomerular permeability, which could be reversed by either an ROS antagonist or by activating the guanylyl cyclase-cGMP pathway. The data strongly suggest a protective effect of NO in maintaining normal glomerular permeability in vivo.
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27.
  • Dolinina, Julia, et al. (författare)
  • Sustained, delayed, and small increments in glomerular permeability to macromolecules during systemic ET-1 infusion mediated via the ETa receptor
  • 2019
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 316:6, s. 1173-1179
  • Tidskriftsartikel (refereegranskat)abstract
    • Dolinina J, Rippe A, Öberg CM. Sustained, delayed, and small increments in glomerular permeability to macromolecules during systemic ET-1 infusion mediated via the ETA receptor. Am J Physiol Renal Physiol 316: F1173–F1179, 2019. First published March 13, 2019; doi:10.1152/ajprenal.00040.2019.—Emerging evidence indicates that endogenous production of endothelin (ET)-1, a 21-amino acid peptide vasoconstrictor, plays an important role in proteinuric kidney disease. Previous studies in rats have shown that chronic administration of ET-1 leads to increased glomerular albumin leakage. The underlying mechanisms are, however, currently not known. Here, we used size-exclusion chromatography to measure glomerular sieving coefficients for neutral FITC-Ficoll (molecular Stokes-Einstein radius: 15–80 Å, molecular weight: 70 kDa/400 kDa) in anesthetized male Sprague-Dawley rats (n = 12) at baseline and at 5, 15, 30, and 60 min after intravenous administration of ET-1. In separate experiments, ET-1 was given together with the selective ET type A (ETA) or ET type B (ETB) receptor antagonists JKC-301 and BQ-788, respectively. At both 15 and 30 min postadministration, the glomerular sieving coefficient for macromolecular Ficoll (70 Å) was significantly increased to 4.4 x 10-5  0.7 x 10-5 (P = 0.024) and 4.5 x 10-5  0.8 x 10-5 (P = 0.007), respectively, compared with baseline (2.2 x 10-5  0.4 x10-5). Decreased urine production after ET-1 prevented the use of higher doses of ET-1. Data analysis using the two-pore model indicated changes in large-pore permeability after ET-1, with no changes in the small-pore pathway. Administration of ETA blocker abrogated the permeability changes induced by ET-1 at 30 min, whereas blockade of ETB receptors was ineffective. Mean arterial pressure was only significantly increased at 60 min, being 123  4 mmHg compared with 111  2 mmHg at baseline (P = 0.02). We conclude that ET-1 evoked small, delayed, and sustained increases in glomerular permeability, mediated via the ETA receptor.
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28.
  • Eckerbom, Per, 1974-, et al. (författare)
  • Circadian variation in renal blood flow and kidney function in healthy volunteers monitored with noninvasive magnetic resonance imaging
  • 2020
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 319:6, s. F966-F978
  • Tidskriftsartikel (refereegranskat)abstract
    • Circadian regulation of kidney function is involved in maintaining whole body homeostasis, and dysfunctional circadian rhythm can potentially be involved in disease development. Magnetic resonance imaging (MRI) provides reliable and reproducible repetitive estimates of kidney function noninvasively without the risk of adverse events associated with contrast agents and ionizing radiation. The purpose of this study was to estimate circadian variations in kidney function in healthy human subjects with MRI and to relate the findings to urinary excretions of electrolytes and markers of kidney function. Phase-contrast imaging, arterial spin labeling, and blood oxygen level-dependent transverse relaxation rate (R2*) mapping were used to assess total renal blood flow and regional perfusion as well as intrarenal oxygenation in eight female and eight male healthy volunteers every fourth hour during a 24-h period. Parallel with MRI scans, standard urinary and plasma parameters were quantified. Significant circadian variations of total renal blood flow were found over 24 h, with increasing flow from noon to midnight and decreasing flow during the night. In contrast, no circadian variation in intrarenal oxygenation was detected. Urinary excretions of electrolytes, osmotically active particles, creatinine, and urea all displayed circadian variations, peaking during the afternoon and evening hours. In conclusion, total renal blood flow and kidney function, as estimated from excretion of electrolytes and waste products, display profound circadian variations, whereas intrarenal oxygenation displays significantly less circadian variation.
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29.
  • Eckerbom, Per, 1974-, et al. (författare)
  • Multiparametric assessment of renal physiology in healthy volunteers using noninvasive magnetic resonance imaging
  • 2019
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 316:4, s. F693-F702
  • Tidskriftsartikel (refereegranskat)abstract
    • Non-invasive methods of magnetic resonance imaging (MRI) can quantify parameters of kidney function. The main purpose of this study was to determine baseline values of such parameters in healthy volunteers. In 28 healthy volunteers (15 females, 13 males), Arterial Spin Labeling (ASL) to estimate regional renal perfusion, Blood Oxygen Level Dependent (BOLD) transverse relaxation rate (R2*) to estimate oxygenation, and Apparent Diffusion Coefficient (ADC), true diffusion (D) and longitudinal relaxation time (T1) to estimate tissue properties were determined bilaterally in the cortex, outer and inner medulla. Additionally, phase contrast (PC) MRI was applied in the renal arteries to quantify total renal blood flow. The results demonstrated profound gradients of perfusion, ADC and D with highest values in the kidney cortex and a decrease towards the inner medulla. R2* and T1 were lowest in kidney cortex and increased towards the inner medulla. Total renal blood flow correlated with body surface area, body mass index and renal volume. Similar patterns in all investigated parameters were observed in females and males. In conclusion, non-invasive MRI provides useful tools to evaluate intra renal differences in blood flow, perfusion, diffusion, oxygenation and structural properties of the kidney tissue. As such, this experimental approach has the potential to advance our current understanding regarding normal physiology and the pathological processes associated with acute and chronic kidney disease.
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30.
  • Edwards, Aurelie, et al. (författare)
  • A model of mitochondrial O-2 consumption and ATP generation in rat proximal tubule cells
  • 2020
  • Ingår i: American Journal of Physiology - Renal Physiology. - : AMER PHYSIOLOGICAL SOC. - 1931-857X .- 1522-1466. ; 318:1, s. F248-F259
  • Tidskriftsartikel (refereegranskat)abstract
    • Oxygen tension in the kidney is mostly determined by O-2 consumption (Qo(2)), which is, in turn, closely linked to tubular Na+ reabsorption. The objective of the present study was to develop a model of mitochondrial function in the proximal tubule (PT) cells of the rat renal cortex to gain more insight into the coupling between Qo(2), ATP formation (G(ATP)), ATP hydrolysis (QATP), and Na+ transport in the PH. The present model correctly predicts in vitro and in vivo measurements of Qo(2), Owns, and ATP and P-i concentrations in PT cells. Our simulations suggest that O-2 levels are not rate limiting in the proximal convoluted tubule, absent large metabolic perturbations. The model predicts that the rate of ATP hydrolysis and cytoplasmic pH each substantially regulate the G AT p-to-Qo(2) ratio, a key determinant of the number of Na+ moles actively reabsorbed per mole of O-2 consumed. An isolated increase in QATP or in cytoplasmic pH raises the GAS-to-Qo(2) ratio. Thus. variations in Na+ reabsorption and pH along the PT may, per se, generate axial heterogeneities in the efficiency of mitochondria' metabolism and Na+ transport. Our results also indicate that the G(AT)(P)-to-Qo(2) ratio is strongly impacted not only by H+ leak permeability. which reflects mitochondrial uncoupling, but also by K+ leak pathways. Simulations suggest that the negative impact of increased uncoupling in the diabetic kidney on mitochondrial metabolic efficiency is partly counterbalanced by increased rates of Na+ transport and ATP consumption. This model provides a framework to investigate the role of mitochondrial dysfunction in acute and chronic renal diseases.
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31.
  • Elvin, Johannes, et al. (författare)
  • Melanocortin 1 Receptor Agonist Protects Podocytes Through Catalase and RhoA Activation.
  • 2016
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 310:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Drugs containing adrenocorticotropic hormone (ACTH) have been used as therapy for patients with nephrotic syndrome. We have previously shown that ACTH and a selective agonist for the melanocortin 1 receptor (MC1R) exert beneficial actions in experimental membranous nephropathy with reduced proteinuria, reduced oxidative stress, improved glomerular morphology and function. Our hypothesis is that MC1R activation in podocytes elicits beneficial effects by promoting stress fibers and maintaining podocyte viability. To test the hypothesis, we cultured podocytes and used highly specific agonists for the MC1R. The podocytes were subjected to the nephrotic-inducing agent puromycin aminonucleoside and downstream effects of MC1R activation on podocyte survival; antioxidant defense and cytoskeleton dynamics were studied. To increase the response and enhance the intracellular signals, podocytes were transduced to overexpress MC1R. We show that puromycin promotes MC1R expression in podocytes and that activation of the MC1R promotes an increase of catalase activity and reduces oxidative stress, which results in dephosphorylation of p190RhoGAP and formation of stress fibers through RhoA. In addition, MC1R agonists protects against apoptosis. Together, these mechanisms protect the podocyte against puromycin. Our findings strongly support the hypothesis that selective MC1R activating agonists protect podocytes and may therefore be useful to treat patients with nephrotic syndromes commonly considered as podocytopathies.
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32.
  • Franzen, Stephanie, et al. (författare)
  • Differences in susceptibility to develop parameters of diabetic nephropathy in four mouse strains with type 1 diabetes
  • 2014
  • Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 306:10, s. F1171-F1178
  • Tidskriftsartikel (refereegranskat)abstract
    • One-third of diabetes mellitus patients develop diabetic nephropathy, and with underlying mechanisms unknown it is imperative that diabetic animal models resemble human disease. The present study investigated the susceptibility to develop diabetic nephropathy in four commonly used and commercially available mouse strains with type 1 diabetes to determine the suitability of each strain. Type 1 diabetes was induced in C57Bl/6, NMRI, BALB/c, and 129Sv mice by alloxan, and conscious glomerular filtration rate, proteinuria, and oxidative stress levels were measured in control and diabetic animals at baseline and after 5 and 10 wk. Histological alterations were analyzed using periodic acid-Schiff staining. Diabetic C57Bl/6 displayed increased glomerular filtration rate, i.e., hyperfiltration, whereas all other parameters remained unchanged. Diabetic NMRI developed the most pronounced hyperfiltration as well as increased oxidative stress and proteinuria but without glomerular damage. Diabetic BALB/c did not develop hyperfiltration but presented with pronounced proteinuria, increased oxidative stress, and glomerular damage. Diabetic 129Sv displayed proteinuria and increased oxidative stress without glomerular hyperfiltration or damage. However, all strains displayed intras-train correlation between oxidative stress and proteinuria. In conclusion, diabetic C57Bl/6 and NMRI both developed glomerular hyperfiltration but neither presented with histological damage, although NMRI developed low-degree proteinuria. Thus these strains may be suitable when investigating the mechanism causing hyperfiltration. Neither BALB/c nor 129Sv developed hyperfiltration although both developed pronounced proteinuria. However, only BALB/c developed detectable histological damage. Thus BALB/c may be suitable when studying the roles of proteinuria and histological alterations for the progression of diabetic nephropathy.
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33.
  • Franzén, Stephanie, et al. (författare)
  • Intrarenal activation of endothelin type B receptors improves kidney oxygenation in type 1 diabetic rats
  • 2018
  • Ingår i: American Journal of Physiology - Renal Physiology. - : AMER PHYSIOLOGICAL SOC. - 1931-857X .- 1522-1466. ; 314:3, s. F439-F444
  • Tidskriftsartikel (refereegranskat)abstract
    • About one-third of patients with type 1 diabetes develops kidney disease. The mechanism is largely unknown, but intrarenal hypoxia has been proposed as a unifying mechanism for chronic kidney disease, including diabetic nephropathy. The endothelin system has recently been demonstrated to regulate oxygen availability in the diabetic kidney via a pathway involving endothelin type A receptors (ETA-R). These receptors mainly mediate vasoconstriction and tubular sodium retention, and inhibition of ETA-R improves intrarenal oxygenation in the diabetic kidney. Endothelin type B receptors (ETB-R) can induce vasodilation of the renal vasculature and also regulate tubular sodium handling. However, the role of ETB-R in kidney oxygen homeostasis is unknown. The effects of acute intrarenal ETB-R activation (sarafotoxin 6c for 30-40 min; 0.78 pmol/h directly into the renal artery) on kidney function and oxygen metabolism were investigated in normoglycemic controls and insulinopenic male Sprague-Dawley rats administered streptozotocin (55 mg/kg) 2 wk before the acute experiments. Intrarenal activation of ETB-R improved oxygenation in the hypoxic diabetic kidney. However, the effects on diabetes-induced increased kidney oxygen consumption could not explain the improved oxygenation. Rather, the improved kidney oxygenation was due to hemodynamic effects increasing oxygen delivery without increasing glomerular filtration or tubular sodium load. In conclusion, increased ETB-R signaling in the diabetic kidney improves intrarenal tissue oxygenation due to increased oxygen delivery secondary to increased renal blood flow.
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34.
  • Franzén, Stephanie, et al. (författare)
  • Postoperative acute kidney injury after volatile or intravenous anesthesia : a meta-analysis
  • 2023
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 324:4, s. F329-F334
  • Tidskriftsartikel (refereegranskat)abstract
    • Postoperative acute kidney injury (AKI) is a common complication after surgery. The pathophysiology of postoperative AKI is complex. One potentially important factor is anesthetic modality. We, therefore, conducted a meta-analysis of the available lit-erature regarding anesthetic modality and incidence of postoperative AKI. Records were retrieved until January 17, 2023, with the search terms ("propofol" OR "intravenous") AND ("sevoflurane" OR "desflurane" OR "isoflurane" OR "volatile" OR "inhala-tional") AND ("acute kidney injury" OR "AKI"). A meta-analysis for common effects and random effects was performed after exclusion assessment. Eight records were included in the meta-analysis with a total of 15,140 patients (n = 7,542 propofol and n = 7,598 volatile). The common and random effects model revealed that propofol was associated with a lower incidence of postoperative AKI compared with volatile anesthesia [odds ratio: 0.63 (95% confidence interval: 0.56-0.72) and 0.49 (95% confidence interval: 0.33-0.73), respectively]. In conclusion, the meta-analysis revealed that propofol anesthesia is associated with a lower incidence of postoperative AKI compared with volatile anesthesia. This may motivate choosing propofol-based anesthesia in patients with increased risk of postoperative AKI due to preexisting renal impairment or surgery with a high risk of renal ischemia. NEW & NOTEWORTHY This study analyzed the available literature on anesthetic modality and incidence of postoperative AKI. The meta-analysis revealed that propofol is associated with lower incidence of AKI compared with volatile anesthesia. It might therefore be considerable to use propofol anesthesia in surgeries with increased susceptibility for developing renal injuries such as cardiopulmonary bypass and major abdominal surgery.
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35.
  • Franzen, Stephanie, et al. (författare)
  • Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice
  • 2016
  • Ingår i: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 310:9, s. F807-F809
  • Tidskriftsartikel (refereegranskat)abstract
    • Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease to be the causal mechanism. To establish whether hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared with normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia 3 days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy.
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36.
  • Friederich-Persson, Malou, 1983-, et al. (författare)
  • Mitochondrial angiotensin II receptors regulate oxygen consumption in kidney mitochondria from healthy and type 1 diabetic rats.
  • 2020
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 318:3, s. 683-688
  • Tidskriftsartikel (refereegranskat)abstract
    • Exaggerated activation of the renin-angiotensin-aldosterone system (RAAS) is a key feature in diseases such as hypertension, diabetes, and chronic kidney disease. Recently, an intracellular RAAS was demonstrated with angiotensin II (ANG II) type 1 (AT1) and type 2 (AT2) receptors expressed in nuclei and mitochondria. Diabetes is associated with both mitochondrial dysfunction and increased intracellular ANG II concentration in the kidney cortex. The present study investigated the role of ANG II signaling in kidney cortex mitochondria isolated from control and streptozotocin-induced diabetic rats. Mitochondrial oxygen consumption was evaluated after addition of ANG II alone or after preincubation with candesartan (AT1 receptor antagonist), PD-123319 (AT2 receptor antagonist), or the two in combination. ANG II binds to only mitochondrial AT2 receptors in control rats and both AT1 receptors and AT2 receptors in diabetic rats. ANG II decreased oxygen consumption in mitochondria from both control and diabetic rats. ANG II response was reversed to increased oxygen consumption by the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester. AT1 receptor inhibition did not affect the response to ANG II, whereas AT2 receptor inhibition abolished the response in mitochondria from control rats and reversed the response to increased oxygen consumption through superoxide-induced mitochondrial uncoupling in mitochondria from diabetic rats. ANG II decrease mitochondrial respiration via AT2 receptor-mediated nitric oxide release in both control and diabetic rats. AT1 receptors do not regulate mitochondria function in control rats, whereas ANG II via AT1 receptors increase mitochondria leak respiration in diabetic animals.
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37.
  • Fähling, Michael, et al. (författare)
  • NFAT5 regulates renal gene expression in response to angiotensin II through Annexin-A2-mediated posttranscriptional regulation in hypertensive rats
  • 2019
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 316:1, s. F101-F112
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim was to identify new targets that regulate gene expression at the posttranscriptional level in angiotensin II (ANGII)-mediated hypertension. Heparin affinity chromatography was used to enrich nucleic acid-binding proteins from kidneys of two-kidney, one-clip (2K1C) hypertensive Wistar rats. The experiment was repeated with 14-day ANGII infusion using Alzet osmotic mini pumps. with or without ANGII receptor AT1a inhibition using losartan in the drinking water. Mean arterial pressure increased after 2K1C or ANGII infusion and was inhibited with losartan. Heparin affinity chromatography and mass spectrometry were used to identify Annexin-A2 (ANXA2) as having differential nucleic acid-binding activity. Total Annexin-A2 protein expression was unchanged, whereas nucleic acid-binding activity was increased in both kidneys of 2K1C and after ANGII infusion through AT1a stimulation. Costaining of Annexin-A2 with alpha-smooth muscle actin and aquaporin 2 showed prominent expression in the endothelia of larger arteries and the cells of the inner medullary collecting duct. The nuclear factor of activated T cells (NFAT) transcription factor was identified as a likely Annexin-A2 target using enrichment analysis on a 2K1C microarray data set and identifying several binding sites in the regulatory region of the mRNA. Expression analysis showed that ANGII increases NFAT5 protein but not mRNA level and, thus, indicated that NFAT5 is regulated by posttranscriptional regulation, which correlates with activation of the RNA-binding protein Annexin-A2. In conclusion, we show that ANGII increases Annexin-A2 nucleic acid-binding activity that correlates with elevated protein levels of the NFAT5 transcription factor. NFAT signaling appears to be a major contributor to renal gene regulation in high-renin states.
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38.
  • Granqvist, Anna, et al. (författare)
  • Podocyte proteoglycan synthesis is involved in the development of nephrotic syndrome
  • 2006
  • Ingår i: Am J Physiol Renal Physiol. - : American Physiological Society. - 0363-6127 .- 1931-857X .- 1522-1466. ; 291
  • Tidskriftsartikel (refereegranskat)abstract
    • Proteoglycans (PG) are important for the glomerular barrier, for cell signaling and for the anchorage of cells to the glomerular basement membrane. They are, however, complex macromolecules, and their production has not yet been thoroughly investigated for podocytes. In the present study, we have studied the biosynthesis of proteoglycans by highly differentiated human podocytes and in rats. The cells were treated with puromycin aminonucleoside (PAN, a nephrosis inducing agent), steroids (used as primary treatment for nephrotic syndrome) or both. Analysis was made by Taqman(R)real-time PCR, Western blot and by metabolic labeling with (35)S and (3)H. We found that podocytes produce versican, syndecan-1, decorin and biglycan together with the previously known PGs syndecan-4, glypican and perlecan. PAN treatment down-regulated the mRNA and the protein expression of both versican (by 24+/-6%, p<0.01, for mRNA and by 50% for protein) and perlecan (by 14+/-5%, p<0.05, for mRNA and by 50% for protein). The decreased expression was confirmed by studying the glomerular gene expression in rats treated with PAN during a time course study. In addition, puromycin decreased the expression of enzymes involved in the glycosaminoglycan (GAG) biosynthesis. Steroid treatment decreased perlecan (by 24+/-3%, p<0.01) and syndecan-1 expression (by 30+/-4%, p<0.01), but increased the expression of decorin 2.5-fold. The observed alterations of proteoglycan synthesis induced by PAN may lead to decreased glomerular anionic charge and disturbed podocyte morphology, factors that are important for the development of a nephrotic syndrome.
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39.
  • Granqvist, Anna, et al. (författare)
  • Primary human glomerular endothelial cells produce proteoglycans, and puromycin affects their posttranslational modification
  • 2005
  • Ingår i: Am J Physiol Renal Physiol. - : American Physiological Society. - 0363-6127 .- 1931-857X .- 1522-1466. ; 288:4
  • Tidskriftsartikel (refereegranskat)abstract
    • This article describes the possible role of the endothelial cell-surface coat, containing proteoglycans (PGs) with connected glycosaminoglycans (GAGs), in maintaining glomerular permselectivity. Primary human glomerular endothelial cells (HGEC) in culture were treated with the nephrosis-inducing agent puromycin aminonucleoside (PAN). Analysis was made by TaqMan real-time PCR, Western blot analysis, and by metabolic labeling with [(35)S]sulfate. The HGECs express several PGs: syndecan, versican, glypican, perlecan, decorin, and biglycan, which may contribute to the glomerular charge barrier. PAN treatment downregulated both the protein expression (by 25%) and the mRNA expression (by 37 +/- 6%, P < 0.001, n = 8) of versican compared with control. Transferases important for chondroitin and heparan sulfate biosynthesis were also significantly downregulated by PAN, resulting in less sulfate groups, shorter GAG chains, and reduced PG net-negative charge. Moreover, analysis of the cell media after PAN treatment revealed a reduced content of [(35)S]sulfate-labeled PGs (40% of control). We conclude that PAN may cause proteinuria by affecting the endothelial cell-surface layer and not only by disrupting the foot process arrangement of the podocytes. Thus the endothelium may be a more important component of the glomerular barrier than hitherto acknowledged.
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40.
  • Grände, Gustaf, et al. (författare)
  • Unaltered Size-selectivity of the Glomerular Filtration Barrier in Caveolin-1 Knock-out (KO) mice.
  • 2009
  • Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 297:2, s. 257-262
  • Tidskriftsartikel (refereegranskat)abstract
    • The transfer of albumin from blood to tissue has been found to be increased in caveolin-1 knock-out (KO) mice. This has been considered to reflect an increased microvascular permeability, conceivably caused by an increased endothelial production of nitric oxide (NO) in mice lacking caveolin-1. To investigate whether such an increase in endothelial NO-production would also affect the glomerular barrier characteristics, the glomerular sieving coefficients () to neutral, polydisperse fluorescein isothiocyanate (FITC)-Ficoll 70/400 (mol. radius 15-90 A) were determined in caveolin-1 KO mice vs. their wild-type counterparts. for Ficoll were assessed using high performance size exclusion chromatography (HPSEC) on blood and urine samples. Furthermore, the transcapillary escape rate (TER) of (125)I-labeled albumin and plasma volume (PV) were determined in both types of mice. Despite an increase in the glomerular filtration rate (GFR) in caveolin-1 KO mice (0.23+/-0.04 mL/min; n=7 vs. 0.10+/-0.02 mL/min; n=7; p<0.05) the glomerular Ficoll sieving curves were nearly identical. Furthermore, caveolin-1 KO mice showed an increased PV (6.59+/-0.42 mL/100g vs. 5.18+/-0.13 mL/100g; p<0.01) but only a tendency of an increased TER (14.69+/-1.59 %/h vs. 11.62+/-1.62 %/h; N.S.). It is concluded that in caveolin-1 KO mice the glomerular permeability was not increased, despite the presence of glomerular hyperfiltration. The present data are in line with the concept that the increased transvascular albumin leakage previously found in mice lacking caveolin-1 may be due to an elevation in systemic microvascular pressure following NO-induced precapillary vasodilatation, rather than being a consequence of an increased microvascular permeability per se. Key words: capillary permeability, nitric oxide, sieving coefficient, Ficoll, glomerular filtration rate.
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41.
  •  
42.
  • Helle, Frank, et al. (författare)
  • Angiotensin II-induced contraction is attenuated by nitric oxide in afferent arterioles from the nonclipped kidney in 2K1C
  • 2009
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 296:1, s. F78-F86
  • Tidskriftsartikel (refereegranskat)abstract
    • Two-kidney, one-clip (2K1C) is a model of renovascular hypertension where we previously found an exaggerated intracellular calcium (Ca(i)(2+)) response to ANG II in isolated afferent arterioles (AAs) from the clipped kidney (Helle F, Vagnes OB, Iversen BM. Am J Physiol Renal Physiol 291: F140-F147, 2006). To test whether nitric oxide (NO) ameliorates the exaggerated ANG II response in 2K1C, we studied ANG II (10(-7) mol/l)-induced calcium signaling and contractility with or without the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME). In AAs from the nonclipped kidney, l-NAME increased the ANG II-induced Ca(i)(2+) response from 0.28 +/- 0.05 to 0.55 +/- 0.09 (fura 2, 340 nm/380 nm ratio) and increased contraction from 80 +/- 6 to 60 +/- 6% of baseline (P < 0.05). In vessels from sham and clipped kidneys, l-NAME had no effect. In diaminofluorescein-FM diacetate-loaded AAs from the nonclipped kidney, ANG II increased NO-derived fluorescence to 145 +/- 34% of baseline (P < 0.05 vs. sham), but not in vessels from the sham or clipped kidney. Endothelial NOS (eNOS) mRNA and ser-1177 phosphorylation were unchanged in both kidneys from 2K1C, while eNOS protein was reduced in the clipped kidney compared with sham. Cationic amino acid transferase-1 and 2 mRNAs were increased in 2K1C, indicating increased availability of l-arginine for NO synthesis, but counteracted by decreased scavenging of the eNOS inhibitor asymmetric dimethylarginine by dimethylarginine dimethylaminohydrolase 2. In conclusion, the Ca(i)(2+) and contractile responses to ANG II are blunted by NO release in the nonclipped kidney. This may protect the nonclipped kidney from the hypertension and elevated ANG II levels in 2K1C.
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43.
  • Helle, Frank, et al. (författare)
  • Nitric oxide in afferent arterioles after uninephrectomy depends on extracellular L-arginine
  • 2013
  • Ingår i: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY. - : American Physiological Society. - 1931-857X .- 1522-1466 .- 0363-6127. ; 304:8, s. F1088-F1098
  • Tidskriftsartikel (refereegranskat)abstract
    • Helle F, Skogstrand T, Schwartz IF, Schwartz D, Iversen BM, Palm F, Hultstrom M. Nitric oxide in afferent arterioles after uninephrectomy depends on extracellular L-arginine. Am J Physiol Renal Physiol 304: F1088-F1098, 2013. First published February 13, 2013; doi: 10.1152/ajprenal.00665.2011.-Uninephrectomy (UNX) causes hyperperfusion of the contralateral remaining kidney via increased nitric oxide (NO) synthesis. Although the exact mechanism remains largely unknown, we hypothesize that this would be localized to the afferent arteriole and that it depends on cellular uptake of L-arginine. The experiments were performed in rats 2 days (early) or 6 wk (late) after UNX and compared with controls (Sham) to study acute and chronic effects on NO metabolism. Renal blood flow was increased after UNX (21 +/- 2 ml.min(-1).kg(-1) in sham, 30 +/- 3 in early, and 26 +/- 1 in late, P andlt; 0.05). NO inhibition with N-omega-nitro-L-arginine methyl ester hydrochloride (L-NAME) caused a greater increase in renal vascular resistance in early UNX compared with Sham and late UNX (138 +/- 24 vs. 88 +/- 10, and 84 +/- 7%, P andlt; 0.01). The lower limit of autoregulation was increased both in early and late UNX compared with Sham (P andlt; 0.05). L-NAME did not affect the ANG II-induced contraction of isolated afferent arterioles (AA) from Sham. AA from early UNX displayed a more pronounced contraction in response to L-NAME (-57 +/- 7 vs. -16 +/- 7%, P andlt; 0.05) and in the absence of L-arginine (-41 +/- 4%, P andlt; 0.05) compared with both late UNX and Sham. mRNA expression of endothelial NO synthase was reduced, whereas protein expression was unchanged. Cationic amino acid transporter-1 and -2 mRNA was increased, while protein was unaffected in isolated preglomerular resistance vessels. In conclusion, NO-dependent hyperperfusion of the remaining kidney in early UNX is associated with increased NO release from the afferent arteriole, which is highly dependent on extracellular L-arginine availability.
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44.
  • Hernandez, Nidia Maritza, 1979, et al. (författare)
  • Antibodies to kidney endothelial cells contribute to a "leaky" glomerular barrier in patients with chronic kidney diseases.
  • 2012
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 302:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Anti-endothelial cell antibodies (AECA) are reported to cause endothelial dysfunction but their clinical importance with tissue specific endothelial cells is not clear. We hypothesized that AECA reactive with human kidney endothelial cells (HKEC) may cause renal endothelial dysfunction in patients with chronic kidney diseases. We found that a (p < 0.001) higher fraction of end-stage renal disease patients (ESRD) (56%) have AECA reactive with glomerular endothelial cells as compared to healthy controls (5%). Presence of antibodies was associated with female sex (p < 0.001), systolic hypertension (p < 0.01) and elevated tumour necrosis factor-alpha (TNF-α, p < 0.05). These antibodies markedly decrease expression of adherens and tight junction proteins VE-cadherin, Claudin-1 and ZO-1 and provoked a rapid increase in cytosolic free Ca(2+) and rearrangement of actin filaments in HKEC as compared to controls, followed by an enhancement in protein flux and phosphorylation of VE-cadherin, events associated with augmented endothelial cell permeability. Staining of kidney biopsies from ESRD patients with AECA but not controls demonstrated a marked decrease in adherens and tight junctions in glomerular endothelium, confirming our in vitro data. In summary, our data demonstrate a causal link between AECA and their capacity to induce alterations in glomerular vascular permeability.
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45.
  • Herrera, Marcela, et al. (författare)
  • Inhibition of T-cell activation by CTLA4-Fc is sufficient to ameliorate proteinuric kidney disease.
  • 2017
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 312:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Diabetic Nephropathy (DN) remains an unmet medical challenge as its prevalence is projected to continue to increase and specific medicines for treatment remain undeveloped. Activation of the immune system, in particular T-cells, is emerging as a possible mechanism underlying DN disease progression in humans and animal models. We hypothesized that inhibition of T-cell activation will ameliorate DN. Interaction of B7-1 (CD80) on the surface of antigen presenting cells with its binding partners, CTLA4 (CD152) and CD28 on T-cells, is essential for T-cell activation. In this study we used the soluble CTLA4-Fc fusion protein Abatacept to block cell surface B7-1, preventing the cellular interaction and inhibiting T-cell activation. When Abatacept was dosed in an animal model of diabetes-induced albuminuria, it reduced albuminuria in both prevention and intervention modes. The number of T-cells infiltrating the kidneys of DN animals correlated with the degree of albuminuria and treatment with Abatacept reduced the number of renal T-cells. As B7-1 induction has been recently proposed to underlie podocyte damage in DN, Abatacept could be efficacious in DN by protecting podocytes. However, this does not appear to be the case as B7-1 was not expressed in: 1) kidneys of DN animals; 2) stimulated human podocytes in culture; or 3) glomeruli of DN patients. We conclude that Abatacept ameliorates DN by blocking systemic T-cell activation and not by interacting with podocytes.
  •  
46.
  • Hofmeister, Marlene Vind, et al. (författare)
  • 17 beta-Estradiol induces nongenomic effects in renal intercalated cells through G protein-coupled estrogen receptor 1
  • 2012
  • Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 302:3, s. 358-368
  • Tidskriftsartikel (refereegranskat)abstract
    • Hofmeister MV, Damkier HH, Christensen BM, Olde B, Leeb-Lundberg LM, Fenton RA, Praetorius HA, Praetorius J. 17 beta-Estradiol induces nongenomic effects in renal intercalated cells through G protein-coupled estrogen receptor 1. Am J Physiol Renal Physiol 302: F358-F368, 2012. First published October 12, 2011; doi: 10.1152/ajprenal.00343.2011.-Steroid hormones such as 17 beta-estradiol (E2) are known to modulate ion transporter expression in the kidney through classic intracellular receptors. Steroid hormones are also known to cause rapid nongenomic responses in a variety of nonrenal tissues. However, little is known about renal short-term effects of steroid hormones. Here, we studied the acute actions of E2 on intracellular Ca2+ signaling in isolated distal convoluted tubules (DCT2), connecting tubules (CNT), and initial cortical collecting ducts (iCCD) by fluo 4 fluorometry. Physiological concentrations of E2 induced transient increases in intracellular Ca2+ concentration ([Ca2+](i)) in a subpopulation of cells. The [Ca2+](i) increases required extracellular Ca2+ and were inhibited by Gd3+. Strikingly, the classic E2 receptor antagonist ICI 182,780 also increased [Ca2+](i), which is inconsistent with the activation of classic E2 receptors. G proteincoupled estrogen receptor 1 (G.PER1 or GPR30) was detected in microdissected DCT2/CNT/iCCD by RT-PCR. Stimulation with the specific GPER1 agonist G-1 induced similar [Ca2+](i) increases as E2, and in tubules from GPER1 knockout mice, E2, G-1, and ICI 182,780 failed to induce [Ca2+](i) elevations. The intercalated cells showed both E2-induced concanamycin-sensitive H+-ATPase activity by BCECF fluorometry and the E2-mediated [Ca2+](i) increment. We propose that E2 via GPER1 evokes [Ca2+](i) transients and increases H+-ATPase activity in intercalated cells in mouse DCT2/CNT/iCCD.
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47.
  • Hultström, Michael, et al. (författare)
  • AT(1) receptor activation regulates the mRNA expression of CAT1, CAT2, arginase-1, and DDAH2 in preglomerular vessels from angiotensin II hypertensive rats.
  • 2009
  • Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1522-1466 .- 1931-857X. ; 297:1, s. F163-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Previously, we found increased expression of l-arginine metabolizing enzymes in both kidneys from two-kidney, one-clip (2K1C) hypertensive rats (Helle F, Hultstrom M, Skogstrand T, Palm F, Iversen BM. Am J Physiol Renal Physiol 296: F78-F86, 2009). In the present study, we investigate whether AT(1) receptor activation can induce the changes observed in 2K1C. Four groups of rats were infused with 80 ng/min ANG II or saline for 14 days and/or given 60 mg x kg(-1) x day(-1) losartan. Gene expression was studied in isolated preglomerular vessels by RT-PCR. Dose-responses to ANG II were studied in isolated preglomerular vessels with and without acute NOS inhibition [10(-4) mol/l N(G)-nitro-l-arginine methyl ester (l-NAME)]. Expressions of endothelial nitric oxide synthase (eNOS), caveolin-1, and arginase-2 were not changed by ANG II infusion. CAT1 (0.3 8 +/- 0.07 to 0.73 +/- 0.12, P < 0.05), CAT2 (1.14 +/- 0.29 to 2.74 +/- 0.48), DDAH2 (1.09 +/- 0.27 to 2.3 +/- 0.46), and arginase-1 (1.08 +/- 0.17 to 1.82 +/- 0.22) were increased in ANG II-infused rats. This was prevented by losartan treatment, which reduced the expression of eNOS (0.97 +/- 0.26 to 0.37 +/- 0.11 in controls; 0.8 +/- 0.16 to 0.36 +/- 0.1 in ANG II-infused rats) and caveolin-1 (2.49 +/- 0.59 to 0.82 +/- 0.24 in controls and 2.59 +/- 0.61 to 1.1 +/- 0.25 in ANG II-infused rats). ANG II (10(-10) mol/l) caused vessels from ANG II-infused animals to contract to 53 +/- 15% of baseline diameter and 90 +/- 5% of baseline diameter in controls (P < 0.05) and was further enhanced by l-NAME to 4 +/- 4% of baseline diameter (P < 0.05). In vivo losartan treatment reduced the reactivity of isolated vessels to 91 +/- 2% of baseline in response to 10(-7) mol/l ANG II compared with 82 +/- 3% in controls (P < 0.05) and prevented the increased responsiveness caused by ANG II infusion. In conclusion, CAT1, CAT2, DDAH2, and arginase-1 expression in renal resistance vessels is regulated through the AT(1) receptor. This finding may be of direct importance for NOS and the regulation of preglomerular vascular function.
  •  
48.
  • Ide, N, et al. (författare)
  • In vivo evidence for an interplay of FGF23/Klotho/PTH axis on the phosphate handling in renal proximal tubules
  • 2018
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 315:5, s. F1261-F1270
  • Tidskriftsartikel (refereegranskat)abstract
    • Phosphate homeostasis is primarily maintained in the renal proximal tubules, where the expression of sodium/phosphate cotransporters (Npt2a and Npt2c) is modified by the endocrine actions of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH). However, the specific contribution of each regulatory pathway in the proximal tubules has not been fully elucidated in vivo. We have previously demonstrated that proximal tubule-specific deletion of the FGF23 coreceptor Klotho results in mild hyperphosphatemia with little to no change in serum levels of FGF23, 1,25(OH)2D3, and PTH. In the present study, we characterized mice in which the PTH receptor PTH1R was specifically deleted from the proximal tubules, either alone or in combination with Klotho ( PT-PTH1R−/−and PT-PTH1R/KL−/−, respectively). PT-PTH1R−/−mice showed significant increases in serum FGF23 and PTH levels, whereas serum phosphate levels were maintained in the normal range, and Npt2a and Npt2c expression in brush border membrane (BBM) did not change compared with control mice. In contrast, PT-PTH1R/KL−/−mice displayed hyperphosphatemia and an increased abundance of Npt2a and Npt2c in the renal BBM, along with increased circulating FGF23 levels. While serum calcium was normal, 1,25(OH)2D3levels were significantly decreased, leading to extremely high levels of PTH. Collectively, mice with a deletion of PTH1R alone in proximal tubules results in only minor changes in phosphate regulation, whereas deletion of both PTH1R and Klotho leads to a severe disturbance, including hyperphosphatemia with increased sodium/phosphate cotransporter expression in BBM. These results suggest an important interplay between the PTH/PTH1R and FGF23/Klotho pathways to affect renal phosphate handling in the proximal tubules.
  •  
49.
  • Ito, Y, et al. (författare)
  • Wolf-Hirschhorn syndrome candidate 1-like 1 epigenetically regulates nephrin gene expression
  • 2017
  • Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 312:6, s. F1184-F1199
  • Tidskriftsartikel (refereegranskat)abstract
    • Altered expression of nephrin underlies the pathophysiology of proteinuria in both congenital and acquired nephrotic syndrome. However, the epigenetic mechanisms of nephrin gene regulation remain elusive. Here, we show that Wolf-Hirschhorn syndrome candidate 1-like 1 long form (WHSC1L1-L) is a novel epigenetic modifier of nephrin gene regulation. WHSC1L1-L was associated with histone H3K4 and H3K36 in human embryonic kidney cells. WHSC1L1-L gene was expressed in the podocytes, and functional protein product was detected in these cells. WHSC1L1-L was found to bind nephrin but not other podocyte-specific gene promoters, leading to its inhibition/suppression, abrogating the stimulatory effect of WT1 and NF-κB. Gene knockdown of WHSC1L1-L in primary cultured podocytes accelerated the transcription of nephrin but not CD2AP. An in vivo zebrafish study involving the injection of Whsc1l1 mRNA into embryos demonstrated an apparent reduction of nephrin mRNA but not podocin and CD2AP mRNA. Immunohistochemistry showed that both WHSC1L1-L and nephrin emerged at the S-shaped body stage in glomeruli. Immunofluorescence and confocal microscopy displayed WHSC1L1 to colocalize with trimethylated H3K4 in the glomerular podocytes. Chromatin immunoprecipitation assay revealed the reduction of the association of trimethylated H3K4 at the nephrin promoter regions. Finally, nephrin mRNA was upregulated in the glomerulus at the early proteinuric stage of mouse nephrosis, which was associated with the reduction of WHSC1L1. In conclusion, our results demonstrate that WHSC1L1-L acts as a histone methyltransferase in podocytes and regulates nephrin gene expression, which may in turn contribute to the integrity of the slit diaphragm of the glomerular filtration barrier.
  •  
50.
  • Jeansson, Marie, 1971, et al. (författare)
  • Morphological and functional evidence for an important role of the endothelial cell glycocalyx in the glomerular barrier
  • 2006
  • Ingår i: Am J Physiol Renal Physiol. - : American Physiological Society. - 0363-6127 .- 1931-857X .- 1522-1466. ; 290:1
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study, we pursued the somewhat controversial issue whether the glycosaminoglycans (GAG) in the endothelial cell glycocalyx are important for glomerular size and charge selectivity. In isoflurane-anesthetized mice, Intralipid droplets were used as indirect markers of the glomerular endothelial cell-surface layer, i.e., the glycocalyx. The mice were given intravenous injections of GAG-degrading enzymes, which due to their high molecular weight remained and acted intravascularly. Flow-arrested kidneys were fixed and prepared for electron microscopy, and the distance between glomerular endothelial cells and the luminal Intralipid droplets was measured. The relative frequency of Intralipid droplets was calculated for each 50-nm increment zone up to 500 nm from the endothelial cell membrane surface as were the mean distances. Glomerular size and charge selectivity were estimated from the clearance data for neutral Ficolls (molecular radii of 12-72 A), and albumin in isolated kidneys was perfused at 8 degrees C. In enzyme-treated animals (hyaluronidase, heparinase, and chondroitinase), the relative Intralipid droplet frequency in the zone closest to the endothelial cells, i.e., 0-50 nm, was increased approximately 2.5 times compared with controls. Also, the mean distance between the Intralipid droplets and the endothelium was decreased from 176 to 115-122 nm by enzyme treatment. These changes were accompanied by an increase in the fractional clearance for albumin. In conclusion, both morphological and functional measurements suggest the endothelial cell glycocalyx to be an important component of the glomerular barrier.
  •  
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