| 1. |
- Axelsson, Josefin, et al.
(författare)
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Reduced diffusion of charge-modified, conformationally intact anionic Ficoll relative to neutral Ficoll across the rat glomerular filtration barrier in vivo
- 2011
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Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 301:4, s. 708-712
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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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| 2. |
- Axelsson, Josefin, et al.
(författare)
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Scavengers of reactive oxygen species, paracalcitol, RhoA and Rac-1 inhibitors and tacrolimus inhibit angiotensin II induced actions on glomerular permeability.
- 2013
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Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 305:3, s. 237-243
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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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| 3. |
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| 4. |
- Dolinina, Julia, et al.
(författare)
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Nitric oxide synthase inhibition causes acute increases in glomerular permeability in vivo, dependent upon reactive oxygen species
- 2016
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Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 311:5, s. 984-990
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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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| 5. |
- Kvale, Reidar, et al.
(författare)
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The Nordic perioperative and intensive care registries-Collaboration and research possibilities
- 2023
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Ingår i: Acta Anaesthesiologica Scandinavica. - : WILEY. - 0001-5172 .- 1399-6576. ; 67:7, s. 972-978
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Nordic perioperative and intensive care registries have been built up during the last 25 years to improve quality in intensive and perioperative care. We aimed to describe the Nordic perioperative and intensive care registries and to highlight possibilities and challenges in future research collaboration between these registries.Material and method: We present an overview of the following Nordic registries: Swedish Perioperative Registry (SPOR), the Danish Anesthesia Database (DAD), the Finnish Perioperative Database (FIN-AN), the Icelandic Anesthesia Database (IS-AN), the Danish Intensive Care Database (DID), the Swedish Intensive Care Registry (SIR), the Finnish Intensive Care Consortium, the Norwegian Intensive Care and Pandemic Registry (NIPaR), and the Icelandic Intensive Care Registry (IS-ICU).Results: Health care systems and patient populations are similar in the Nordic countries. Despite certain differences in data structure and clinical variables, the perioperative and intensive care registries have enough in common to enable research collaboration. In the future, even a common Nordic registry could be possible.Conclusion: Collaboration between the Nordic perioperative and intensive care registries is both possible and likely to produce research of high quality. Research collaboration between registries may have several add-on effects and stimulate international standardization regarding definitions, scoring systems, and benchmarks, thereby improving overall quality of care.
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| 6. |
- Sverrisson, Kristinn, et al.
(författare)
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Acute, Reactive Oxygen Species (ROS) dependent effects of IL-1β, TNF-α, and IL-6 on the glomerular filtration barrier (GFB) in vivo.
- 2015
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Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 309:9, s. 800-806
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Tidskriftsartikel (refereegranskat)abstract
- This study was performed in order to investigate the immediate actions of the proinflammatory cytokines, interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), on the permeability of the glomerular filtration barrier (GFB) in rats and to test whether these actions are dependent upon the release of reactive oxygen species (ROS). In anaesthetized rats blood access was achieved and the left ureter was cannulated for urine collection. Rats were continuously infused i.v. with either IL-1β (0.4 and 2 μg·kg(-1)·h(-1)), TNF-α (0.4 and 2 μg·kg(-1)·h(-1)) or IL-6 (4 and 8 μg·kg(-1)·h(-1)), together with polydisperse fluorescein isothiocyanate (FITC)-Ficoll-70/400 and Inulin for 1 h. Plasma and urine samples were analyzed by high performance size exclusion chromatography (HPSEC) for determination of glomerular sieving coefficients (θ). The glomerular filtration rate (GFR) was also assessed ((51)Cr-EDTA). In separate experiments the superoxide scavenger, tempol (30 mg·kg(-1)·h(-1)), was given before and during cytokine infusions. IL-1β and TNF-α caused rapid, partly reversible increases in glomerular permeability to large molecules (Ficoll50-80Å), peaking at 5-30 min, while IL-6 caused a more gradual increase in permeability, leveling off at 60 min. Tempol almost completely abrogated the glomerular permeability effects of the cytokines infused. In conclusion IL-1β, TNF-α and IL-6, when infused systemically, caused immediate and partly reversible increases in glomerular permeability, which could be inhibited by the superoxide scavenger, tempol, suggesting an important role of ROS in acute cytokine induced permeability changes of the GFB.
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| 7. |
- Sverrisson, Kristinn, et al.
(författare)
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Dynamic, size-selective effects of protamine sulfate and hyaluronidase on the rat glomerular filtration barrier in vivo.
- 2014
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Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 307:10, s. 1136-1143
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Tidskriftsartikel (refereegranskat)abstract
- The proteinuric actions of protamine sulfate (PS) have classically been, at least partly, attributed to alterations of the negatively charged glomerular endothelial glycocalyx (GC). To investigate whether the charge-selective properties of the glomerular filtration barrier (GFB) would be altered by PS we assessed the glomerular sieving of conventional, uncharged, polydispersed Ficoll (n-Ficoll) compared to charge modified, conformationally intact, anionic (carboxymethylated) Ficoll (a-Ficoll) before and after systemic infusions of PS in rats. For comparison we also investigated the impact of hyaluronidase (Hyase), which partially degrades the GC, on GFB permeability. In anaesthetized Wistar rats blood access was achieved and the left ureter was cannulated for urine collection. Rats were infused with either n-Ficoll or a-Ficoll before and during systemic infusions with either PS or Hyase. Plasma and urine samples were taken repeatedly and analyzed by high performance size exclusion chromatography (HPSEC) for assessing glomerular sieving coefficients (θ) for Ficoll (radius 10-80Å). The GFB showed a significant glomerular charge selectivity for Ficoll molecules of radius 20-35Å (Ficoll20-35Å). PS and Hyase infusions reversibly increased θ for large Ficoll molecules (Ficoll50-80Å). Thus, for PS θ for a-Ficoll70Å increased from 2.47 x 10(-5) ± 1.1(-5) to 7.25 x 10(-5) ± 1.1(-5) (P<0.05) at 15 min. For Hyase the changes in a-Ficoll50-80Å were, however, not statistically significant. Neither PS nor Hyase had any effect on θ for n-Ficoll20-45Å or a-Ficoll20-45Å. It is concluded that systemically administered PS and Hyase in moderate doses dynamically decreased the size-selectivity of the rat GFB without affecting its charge selective properties.
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| 8. |
- Sverrisson, Kristinn, et al.
(författare)
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Extracellular fetal hemoglobin induces increases in glomerular permeability: inhibition with alfa-1-microglobulin and tempol
- 2014
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Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 306:4, s. 442-448
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular fetal hemoglobin (HbF) and adult hemoglobin (HbA) are proinflammatory and generate ROS. Increased plasma levels of extracellular HbF have recently been reported to occur in early preeclampsia. α1-Microglobulin (A1M) is a physiological heme-binding protein and radical scavenger that has been shown to counteract vascular permeability increases induced by HbA in the perfused placenta. The present study was performed to investigate whether HbF and HbA will increase glomerular permeability in vivo and to test whether A1M and tempol, a ROS scavenger, can prevent their effects. Anesthetized Wistar rats were continuously infused intravenously with either HbA, HbF, or cyano-inactivated HbF together with FITC-Ficoll-70/400, inulin, and51Cr-labeled EDTA for 2 h. Plasma samples and urine samples (left ureter) were taken repeatedly and analyzed by high-performance size exclusion chromatography to assess glomerular sieving coefficients for Ficoll of radius 10–80 Å. In separate experiments, A1M or tempol was given before and during Hb infusions. Extracellular HbF caused rapid, transient increases in glomerular permeability to large Ficoll molecules (50–80Å), contrary to the effects of HbA and cyano-inactivated HbF. For HbF, glomerular sieving coefficients for Ficoll of radius 60Å increased from 3.85 ± 0.85 × 10−5to 2.60 ± 0.96 × 10−4at 15 min, changes that were abrogated by tempol and reduced by A1M. In conclusion, our data demonstrate that extracellular HbF, infused systemically, can acutely increase glomerular permeability through inducing oxidative stress.
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| 9. |
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| 10. |
- Sverrisson, Kristinn
(författare)
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Physiological aspects of the glomerular filtration barrier
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Proteinuria is associated with progression of kidney disease and is an independent risk factor for cardiovascular morbidity and mortality. The pathophysiological alterations resulting in proteinuria are obscure, although proteinuria is often associated with pathological changes in the glomerular filtration barrier (GFB). It is therefore of great interest to study the physiology of the GFB, in order to be able to prevent or reduce proteinuria. The studies in this thesis were performed using an in vivo model in anesthetized rats. The rats were cannulated for blood access and the left ureter cannulated for urine collection through a small abdominal incision. The glomerular permeability was measured using sieving coefficients (θ) for fluorescently labeled Ficoll (FITC-Ficoll) with a molecular radius ranging from 10Å to 80Å. The rats were infused with FITC-Ficoll, and blood- and urine samples were collected and analyzed with high performance size exclusion chromatography (HPSEC). In study I, the GFB charge-selectivity was explored using a negatively charged, conformationally intact anionic Ficoll (CMI-Ficoll), comparing it to neutral Ficoll, of same Stokes-Einstein (SE) radius. The sieving of CMI-Ficoll was reduced across the GFB compared to neutral Ficoll for molecules of radius 20-35Å. The GFB was thus found to be negatively charged. However, the charge was of much less magnitude than previously estimated. In study II, the proposed effects of systemic infusion of protamine sulfate (PS) and hyaluronidase (Hyase) on the GFB charge-selectivity were studied. PS and to some extent Hyase, increased the permeability for Ficoll molecules > 50Å, but had no effect on the charge-selectivity of the GFB. In study III, the permeability effects of extracellular adult (HbA) and fetal hemoglobin (HbF) were studied, showing increases in θ for macromolecules (50-80Å in radius) after infusion of HbF, but not after HbA or cyano-inactivated HbF (CN-HbF) infusions. Tempol (a superoxide radical scavenger) and α-1-microglobulin (A1M; a physiological hemebinding protein and radical scavenger), both prevented the increase in the permeability of the GFB. In study IV, the effects of the pro-inflammatory cytokines, TNF-α, Il-1β and IL-6, on the GFB permeability were studied. TNF-α and Il-1β caused a rapid, reversible, increase in glomerular permeability, while IL-6 generated a more gradual response. These effects could be inhibited with tempol, showing a reactive oxygen species (ROS) dependency of the cytokine effects on the GFB permeability.
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