| 1. |
- Rippe, Catarina, et al.
(författare)
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Nature of glomerular capillary permeability changes following acute renal ischemia/reperfusion (I/R) injury in rats.
- 2006
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Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 291:6, s. 1362-1368
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Tidskriftsartikel (refereegranskat)abstract
- This study was performed to evaluate the alterations of glomerular filtration barrier characteristics following acute renal ischemia-reperfusion (I/R). Ischemia was induced in anesthetized rats by unilateral renal artery occlusion for either 20 or 60 min, followed by reperfusion during 20 or 60 min, respectively, with the contralateral kidney serving as control. Sieving coefficients (theta) were obtained by analyzing Ficoll [mol.radius (a(e)) 13-85 angstrom] in urine and plasma after 20 and 60 min I/R. Furthermore, theta for human serum albumin (HSA) was estimated using a tissue uptake technique after 20 and 60 min of I/R, while clearance of HSA compared with that for neutralized HSA (nHSA) was assessed after 20 min of I/R only. Glomerular filtration rate (GFR) was measured by [Cr-51] EDTA and inulin. I/R reduced GFR and increased theta for Ficoll molecules of a(e) > 55 angstrom and theta for albumin. theta for Ficoll vs. a(e), analysed using a two-pore model, demonstrated that, despite increases in theta, the large-pore fractional ultrafiltration coefficient (alpha(L)) was unchanged after 20 min of I/R, owing to the decline in GFR, but increased after 60 min of I/R. However, the apparent alpha(L) for albumin increased already after 20 min of I/R (P < 0.005) and the nHSA/HSA clearance ratio was slightly reduced, possibly reflecting a diminished negative charge barrier. In conclusion, after 20 min of I/R, indications of a reduced charge selectivity were noted, while after 60 min of I/R, there was mainly a reduction in size selectivity, compatible with an increased formation of large pores.
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| 2. |
- Albinsson, Sebastian, et al.
(författare)
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Arterial remodeling and plasma volume expansion in caveolin-1 deficient mice.
- 2007
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 293, s. 1222-1231
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Tidskriftsartikel (refereegranskat)abstract
- Caveolin- 1 ( Cav- 1) is essential for the morphology of membrane caveolae and exerts a negative influence on a number of signaling systems, including nitric oxide ( NO) production and activity of the MAP kinase cascade. In the vascular system, ablation of caveolin- 1 may thus be expected to cause arterial dilatation and increased vessel wall mass ( remodeling). This was tested in Cav- 1 knockout ( KO) mice by a detailed morphometric and functional analysis of mesenteric resistance arteries, shown to lack caveolae. Quantitative morphometry revealed increased media thickness and media- to- lumen ratio in KO. Pressure- induced myogenic tone and flow- induced dilatation were decreased in KO arteries, but both were increased toward wild- type ( WT) levels following NO synthase ( NOS) inhibition. Isometric force recordings following NOS inhibition showed rightward shifts of passive and active length- force relationships in KO, and the force response to alpha 1- adrenergic stimulation was increased. In contrast, media thickness and force response of the aorta were unaltered in KO vs. WT, whereas lumen diameter was increased. Mean arterial blood pressure during isoflurane anesthesia was not different in KO vs. WT, but greater fluctuation in blood pressure over time was noted. Following NOS inhibition, fluctuations disappeared and pressure increased twice as much in KO ( 38 +/- 6%) compared with WT ( 17 +/- 3%). Tracer- dilution experiments showed increased plasma volume in KO. We conclude that NO affects blood pressure more in Cav- 1 KO than in WT mice and that restructuring of resistance vessels and an increased responsiveness to adrenergic stimulation compensate for a decreased tone in Cav- 1 KO mice.
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| 3. |
- Grände, Gustaf, et al.
(författare)
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Unaltered Size-selectivity of the Glomerular Filtration Barrier in Caveolin-1 Knock-out (KO) mice.
- 2009
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Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 297:2, s. 257-262
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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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| 4. |
- Rippe, Anna, et al.
(författare)
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Disproportionally low clearance of macromolecules from the plasma to the peritoneal cavity in a mouse model of peritoneal dialysis (PD).
- 2007
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Ingår i: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 22:1, s. 88-95
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Tidskriftsartikel (refereegranskat)abstract
- Background. This study was performed to establish a model for quantitative measurements of a number of basic peritoneal transport parameters, particularly transperitoneal clearances (Cl) of macromolecules, during mouse peritoneal dialysis. Methods. Mice were anaesthetized using 3% isofluorane inhalation anaesthesia. The right jugular vein and the left femoral artery were cannulated for infusion and sampling purposes and for registration of (mean) arterial blood pressure. Access to the peritoneal cavity occurred via a thin abdominal catheter (Ø 0.7 mm). About 2.5 ml of either 4% (n = 9) or 1.5% (n = 5) glucose containing PD-fluid were instilled intraperitoneally (i.p.). Dialysate volume was followed vs time using i.p. RISA (125I human serum albumin) as a volume marker, after correcting for RISA mass disappearance from the peritoneum, assessed separately (n = 11). Microsampling (10 µl) of plasma and dialysate was performed for determinations of glucose, haematocrit, radioactivity (RISA and 51Cr-EDTA) and Ficoll. Results. The i.p. volume vs time curves [VD(t)] were, after scaling, similar to those observed in humans (and in rats). Clearance of RISA out of the peritoneal cavity (Clout) was 9.33 ± 0.83 µl/min and the clearance of RISA to plasma (Cl->P) and the RISA clearance to the peritoneal cavity (Cl->D) were 1.49 ± 0.13 and 0.084 ± 0.008 µl/min, respectively. The peritoneal transport coefficients for 51Cr-EDTA and glucose, as well as Clout and Cl->P, were 13–17% of those previously assessed in 300 g rats, whereas Cl->D was only ~2% of that in rat. Conclusions. All peritoneal transport parameters measured, except Cl->D, scaled very well to the corresponding human data. The mechanisms of the disproportionally low clearance of macromolecules from the plasma to the peritoneal cavity in mice remain elusive and warrant further study.
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| 5. |
- Rippe, Catarina, et al.
(författare)
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Effects of glomerular filtration rate on Ficoll sieving coefficients (theta) in rats.
- 2006
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Ingår i: Kidney International. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 69:8, s. 1326-1332
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to assess the role of diffusion and convection during filtration of Ficoll across the glomerular filter by comparing glomerular sieving coefficients ( h) to neutral fluorescein isothiocyanate ( FITC)-Ficoll 70/400 obtained at low ( hydropenic) vs raised ( normal) glomerular filtration rates (GFRs). The h for FITC-Ficoll was determined in anesthetized Wistar rats (304 +/- 18 g) following laparotomy and cannulation of the ureters, used for urine sampling. After surgery, GFR was 1.2 +/- 0.16 ml/ min (+/- s. e.), assessed using the plasma to urine clearance of FITC-inulin and Cr-51-ethylenediaminetetraacetic acid. FITC-Ficoll 70/400 was infused intravenously (i.v.) following an initial bolus dose. To raise GFR, to an average of similar to 2 ml/ min, 5 ml of serum together with glucagon ( 3 mu g/min) was given i.v. FITC- inulin and FITC- Ficoll were determined in plasma and urine using size-exclusion high-performance liquid chromatography. The h for Ficoll as a function of Stokes - Einstein radius was significantly reduced in the range of 13 - 43 angstrom when GFR was raised. The maximal h lowering effect, in relative terms, of raising GFR was obtained for a Ficoll a(e) of similar to 32 angstrom. For Ficoll(36 angstrom) (cf. albumin), h was reduced from 0.111 +/- 0.009 to 0.081 +/- 0.012 ( P<0.05; n = 7) for the GFR increment imposed. The reduction in h for Ficoll after raising GFR indicates the presence of a high diffusive component of glomerular Ficoll filtration in rats in vivo and contradicts the notion of a significant concentration polarization effect in the glomerular filter upon Ficoll molecules <50 angstrom in radius.
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| 6. |
- Rippe, Catarina, et al.
(författare)
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Size and charge selectivity of the glomerular filter in early experimental diabetes in rats
- 2007
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Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 293:5, s. 1533-1538
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Tidskriftsartikel (refereegranskat)abstract
- Microalbuminuria is an early sign of diabetic nephropathy. The aim of the present study was to investigate whether the changes of the glomerular filtration barrier in early experimental diabetes are due to size- or charge-selective alterations. Wistar rats, made diabetic by streptozotocin (STZ) and having their blood glucose maintained at similar to 20 mM for 3 or 9 wk, were compared with age-matched controls. Glomerular clearances of native albumin (C1-HSA) and neutralized albumin (C1-nHSA) were assessed using a renal uptake technique. Glomerular filtration rate and renal plasma flow were assessed using Cr-51-EDTA and [ I-125]iodohippurate, respectively. In a separate set of animals, diabetic for 9 wk, and in controls, glomerular sieving coefficients (theta) for neutral FITC-Ficoll (molecular radius: 15-90 angstrom) were assessed using size exclusion chromatography. At 3 wk of diabetes, C1-HSA and C1-nHSA remained unchanged, indicating no alteration in either size or charge selectivity. By contrast, at 9 wk of diabetes, there was a twofold increase of C1-HSA, whereas C1-nHSA remained largely unchanged, at first suggesting a glomerular charge defect. However, according to a two-pore model, the number of large pores, assessed from both Ficoll and C1-HSA, increased twofold. In addition, a small reduction in proximal tubular reabsorption was observed at 3 wk, which was further reduced at 9 wk. In conclusion, no functional changes were observed in the glomerular filtration barrier at 3 wk of STZ-induced diabetes, whereas at 9 wk there was a decrease in size selectivity due to an increased number of large glomerular pores.
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| 7. |
- Rosengren, Bert-Inge, et al.
(författare)
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Transvascular protein transport in mice lacking endothelial caveolae.
- 2006
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Ingår i: American Journal of Physiology: Heart and Circulatory Physiology. - : American Physiological Society. - 1522-1539 .- 0363-6135. ; 291:3, s. 1371-1377
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Tidskriftsartikel (refereegranskat)abstract
- Caveolae are Omega-shaped vesicular structures postulated to play a role in transvascular protein transport. Studies on mice lacking endothelial caveolae, caveolin-1 knockout (Cav-1-KO) mice, indicate increased macromolecular transport rates. This was postulated to be due to the appearance of an alternative pathway. The present study tested whether an alternative pathway had appeared in Cav-1-KO mice. Male Cav-1-KO (n=12) and male control mice (n=13) were intubated and anesthetized using 2% isoflurane. I-125-labeled albumin, I-131-labeled immunoglobulin M (IgM), and polydisperse FITC-Ficoll were administered intravenously. During tracer administration, a 90-min peritoneal dialysis dwell was performed. Clearance of tracers to dialysate and permeability-surface area product for glucose were assessed. Transvascular protein transport was higher in Cav-1-KO compared with control mice. Albumin clearance from plasma to peritoneum was 0.088 +/- 0.008 mu l/min in control and 0.179 +/- 0.012 mu l/min in Cav-1-KO (P = 0.001) mice. IgM clearance was 0.049 +/- 0.003 and 0.083 +/- 0.010 mu l/min in control and Cav-1-KO mice, respectively (P = 0.016). Ficoll clearance was increased in Cav-1-KO mice. In conclusion, the lack of caveolae in Cav-1-KO mice resulted in a marked increase in macromolecular transport. A two-pore analysis of the Ficoll clearance data revealed that the higher transport rate in Cav-1-KO mice was not compatible with the appearance of an alternative pathway for macromolecular transport. In contrast, the higher transperitoneal protein and Ficoll clearance is consistent with passive porous transport through an unperturbed two-pore system, presumably at an elevated capillary hydraulic pressure. Alternatively, the data may be explained by reductions in the selectivity of the endothelial glycocalyx, leading to an increased capillary hydraulic conductivity and large solute filtration.
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| 8. |
- Axelsson, Josefin, et al.
(författare)
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Acute hyperglycemia induces rapid, reversible increases of glomerular permeability in non-diabetic rats.
- 2010
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Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 298:6, s. 1306-1312
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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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| 9. |
- Axelsson, Josefin, et al.
(författare)
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Effects of early endotoxemia and dextran-induced anaphylaxis on the size-selectivity of the glomerular filtration barrier in rats.
- 2009
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Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 296:2, s. 242-248
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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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| 10. |
- Axelsson, Josefin, et al.
(författare)
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Loss of size-selectivity of the glomerular filtration barrier in rats following laparotomy and muscle trauma.
- 2009
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Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 297, s. 577-582
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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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