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      Glomerular Basement Membrane Anionic Sites in Adriamycin Nephropathy: Effect of Saline Loading and Nitric Oxide Modulation

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          Abstract

          Background: In previous studies we found that experimental Adriamycin (ADR) nephropathy is associated with the loss of glomerular basement membrane (GBM) anionic sites provided by heparan sulfate proteoglycans. Chronic saline loading in normal rats resulted in a similar effect on the GBM anionic sites. The L-arginine-nitric oxide synthase-nitric oxide system is involved in the pathogenesis of experimental chronic renal failure. The present study was performed to determine the combined effect of nitric oxide (NO) modulation and chronic saline loading in ADR nephropathy. The modulation of NO was done by chronic administration of L-arginine (NO donor) or N<sup>w</sup>-nitro- L-arginine, a known nitric oxide synthase inhibitor. Methods: Systolic blood pressure was measured in awake rats by a tail-cuff method. Renal function was assessed by creatinine clearance, FeNa%, and daily protein excretion. The change of mean GBM widths and anionic sites distribution were assessed by electron microscopy. The localization of anionic sites was carried out by cationic colloidal gold. Plasma and urinary nitrates (NO<sub>x</sub>) were measured by nitrite (NO<sub>2</sub>) + nitrate (NO<sub>3</sub>), stable metabolites of NO. Results: Two weeks after the ADR administration (3.5 mg/kg BW iv) the rats had severe renal failure (creatinine clearance 134 ± 31 µl/min/100 g BW vs. initial values 670 ± 29 µl/min/ 100 g BW, p < 0.001), high FeNa%, severe proteinuria, increased GBM width, significant reduction of GBM anionic sites and low urinary NO<sub>x</sub> excretion. The saline loading resulted in further reduction of GBM anionic sites count and blood pressure elevation. The inhibition of NO did not change the course of ADR nephropathy. The main finding of the present study is that chronic administration of L-arginine significantly alleviates the renal failure in the ADR (+/– saline loading) nephropathy. The L-arginine-treated rat had higher creatinine clearance, lower FeNa% and protein excretion and complete normalization of GBM anionic sites distribution. Conclusions: Sodium loading has a deleterious effect on GBM permselectivity. L-Arginine prevents the reduction of GBM anionic sites, decreases proteinuria and alleviates the renal insufficiency in ADR nephropathy.

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          Endothelium-derived relaxing factor

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            Low Nitric Oxide Production in Patients with Chronic Renal Failure

            Background: Rats with chronic renal failure have a low nitric oxide (NO) production and a diminished NO excretion. The supplementation of L -arginine has an inhibitory effect on the progression of renal insufficiency. Methods: The present study was designed to determine whether chronic renal failure patients have a low NO production. Plasma and urine nitrate (NO 3 ) and nitrite (NO 2 ), stable metabolites of NO, were measured in 83 consecutive patients with chronic renal failure. The 83 chronic renal failure patients were divided into three groups: group 1, mild renal failure (creatinine clearance >60 ml/min/1.73 m 2 ); group 2, moderate renal failure (creatinine clearance >30 2 ), and group 3, severe renal failure (creatinine clearance 2 ). Thirty-three healthy volunteers served as controls. Results: The daily urinary NO excretion was significantly lower in patients with moderate and severe renal failure as compared with those with mild renal failure and normal controls. The lowest values were found in the severe renal failure group. When the 24-hour urinary NO excretion or NO per milligram creatinine and the NO clearance were correlated with the renal function in all patients as a group, these parameters were directly correlated with the creatinine clearance and inversely correlated with the serum creatinine level. The plasma NO concentration was not different between the three chronic renal failure groups, but higher than in the controls. Plasma NO in renal failure patients was not correlated with the creatinine clearance or serum creatinine levels. Conclusions: Chronic renal failure is a state of NO deficiency. Treatment strategies to increase NO production ( L -arginine supplementation or other NO compounds) may prove to be useful in maintaining the renal function and slow the progression of renal disease.
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              Experimental Focal Segmental Glomerulosclerosis in Mice

              Although a lot of animal models of proteinuria have been established, proposals for the mechanisms of proteinuria are still controversial. In this work, during an 18-day trial, mice injected with a single dose of adriamycin (AD) rapidly showed combined glomerular albuminuria and immunoglobulinuria, progressively elevated levels of nitrite/nitrate in urine, hypercholesterolemia, abnormal renal function, segmentally or globally glomerular hyalinosis/sclerosis associated with tubular atrophy, enhanced glomerular deposition of immunoglobulins and fibrinogen, augmented expression of matrix components in the whole glomerular tuft, and loss of glomerular negative charge property. These laboratory and pathological features are comparatively similar to those of human focal segmental glomerulosclerosis in the advanced state. Juxtamedullary glomeruli appear to be more susceptible to the AD-related nephrotoxicity than those in the superficial renal cortex. A change in size-dependent glomerular permselectivity may precede a charge-dependent defect in glomeruli in this mouse model of proteinuria. Data in this study confirm the hypothesis of glomerular hyperfiltration involved in the pathogenesis of this chronic glomerulopathy associated with proteinuria in mice. In addition, nitric oxide may play a crucial role in the progression of the chronic glomerulopathy model.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2000
                April 2000
                30 March 2000
                : 84
                : 4
                : 354-361
                Affiliations
                aDepartment of Nephrology, Ichilov, Tel-Aviv and Sackler Medical School, Tel-Aviv University; bDepartment of Pathology, Sackler Medical School, Tel-Aviv University, and cDepartment of Pathology, Sheba Medical Center, Tel-Hashomer, Israel
                Article
                45611 Nephron 2000;84:354–361
                10.1159/000045611
                10754413
                © 2000 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Tables: 3, References: 47, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/45611
                Categories
                Original Paper

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