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      Reversible Angiotensin II-Mediated Albuminuria in Rat Kidneys Is Dynamically Associated with Cytoskeletal Organization

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          Abstract

          Angiotensin II (ANG II) is intimately involved in normal renal function, and is estimated to exist at a normal physiological range of 6–10 n M within the renal tubules. The potential role that intrarenal ANG II may play in renal disease was assessed by perfusing isolated rat kidneys with or without excess intratubular levels of ANG II, which may mimic changes in the intrarenal RAS under pathological conditions. The effects of increased systemic ANG II were also determined by infusing rats with ANG II by osmotic pump. In isolated perfused kidneys, ANG II significantly and specifically increased the fractional clearance of albumin to clinical levels, as determined by using radiolabelled albumin. This effect was reversible, as removing ANG II from the perfusate caused the albumin fractional clearance to decrease to pre-ANG II exposure levels. The increase in fractional clearance of albumin was not correlated with renal hemodynamic changes, nor glomerular permeability alterations as measured by the fractional clearance of 36 Å Ficoll and immunoglobulin G. Immunochemical analysis using anti-α-tubulin antibody of perfused kidney sections revealed that ANG II caused a marked disruption of tubular epithelial cytoskeletal components, through disassembly and reorganization of α-tubulin. This disruption was reversible. In vivo, osmotic pump delivery of ANG II at less potent dosage caused a proteinuria (Biuret) and an albuminuria (radioimmunoassay) in rats, from as early as 2 days after pump implantation. These results demonstrate that ANG II may reversibly induce clinical levels of albuminuria. These data point to an important role for renal tubules and the intratubular lumen concentrations of ANG II in the renal processing of albumin.

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          Most cited references 8

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          Pathogenesis, prevention, and treatment of diabetic nephropathy.

           M. J. Cooper (1998)
          It is likely that the pathophysiology of diabetic nephropathy involves an interaction of metabolic and haemodynamic factors. Relevant metabolic factors include glucose-dependent pathways such as advanced glycation, increased formation of polyols, and activation of the enzyme, protein kinase C. Specific inhibitors of the various pathways are now available, enabling investigation of the role of these processes in the pathogenesis of diabetic nephropathy and potentially to provide new therapeutic approaches for the prevention and treatment of diabetic nephropathy. Haemodynamic factors to consider include systemic hypertension, intraglomerular hypertension, and the role of vasoactive hormones, such as angiotensin II. The mainstay of therapy remains attaining optimum glycaemic control. Antihypertensive therapy has a major role in slowing the progression of diabetic nephropathy. Agents that interrupt the renin-angiotensin system such as angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists may be particularly useful as renoprotective agents in both the hypertensive and normotensive context.
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            Podocyte foot process broadening in experimental diabetic nephropathy: amelioration with renin-angiotensin blockade.

            Changes in podocyte number and morphology have been implicated in the pathogenesis of proteinuria and the progression of human and experimental kidney disease. This study sought to examine podocyte foot process and slit pore architecture in experimental diabetic nephropathy and to determine whether such changes were modified with renoprotective intervention by blockade of the renin-angiotensin system. The number of filtration slits per 100 microm of glomerular basement membrane was assessed by transmission electron microscopy and quantitated histomorphometrically in control animals and in rats with 24 weeks of streptozotocin-induced diabetes. Diabetic rats were either untreated or received the angiotensin converting enzyme inhibitor ramipril, or the angiotensin II type 1 receptor antagonist, valsartan. When compared with control animals, diabetes was associated with a decrease in the number of slit pores per unit length of glomerular basement membrane, indicative of podocyte foot process broadening. Both ramipril and valsartan attenuated these ultrastructural changes to a similar degree. These differences remained after correcting for glomerular volume as a possible confounding variable. Preservation of podocyte architecture could contribute to the renoprotective effects of renin-angiotensin system blockade in diabetic nephropathy.
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              Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy.

              The degree of proteinuria in patients with diabetes correlates strongly with both an increase in progression of nephropathy as well as cardiovascular events. Moreover, post hoc analyses of recent clinical trials support the concept that reductions of blood pressure and proteinuria correlate with a slowed progression of nephropathy. Both angiotensin converting enzyme (ACE) inhibitors and the nondihydropyridine calcium antagonists, (non-DHPCAs) reduce both arterial pressure and proteinuria in those with diabetic nephropathy. The present randomized, open label, parallel group designed study tests the hypothesis that, at similar levels of blood pressure, the combination of an ACE inhibitor, trandolapril (T) with the non-DHPCA, verapamil (V) produces a greater reduction in proteinuria over either agent alone at one year. Thirty-seven participants, mean age 59.6 +/- 5.8 years, with nephropathy (baseline creatinine 1.4 +/- 0.3 mg/dl and proteinuria of 1342 +/- 284 mg/dl) secondary to type 2 diabetes completed the study. Doses of drug were titrated in each group over eight weeks to achieve a goal blood pressure of < 140/90 mm Hg. All participants were counseled to ingest a sodium diet of < 120 mEq/day. Proteinuria reduction from baseline was significantly greater in the T+V group compared to either T alone (-33 +/- 8%, T vs. -62 +/- 10%, T+V; P < 0.001) or V alone (-27 +/- 8%, V vs. -62 +/- 10%, T+V; P < 0.001). No significant differences in either glomerular filtration rate, arterial pressure, fasting blood glucose or urinary sodium excretion were noted at one year. The mean daily dose of the individual components of T+V (2.9 +/- 0.8 mg, T/219 +/- 21.1 mg V) was significantly lower than the dose of either T alone 5.5 +/- 1.1 mg/day (P < 0.01) or V alone 314.8 +/- 46.3 mg, given in two divided doses (P < 0.01). These data support the concept that the combination of an ACE inhibitor with a non-DHPCA reduce proteinuria to a greater extent than either agent alone. This added antiproteinuric effect occurs at lower doses of each drug and is independent of further reductions in arterial pressure. These findings could have ramifications for slowing renal disease progression in patients with nephropathy from type 2 diabetes.
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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2003
                February 2003
                20 February 2003
                : 93
                : 2
                : p51-p60
                Affiliations
                aDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., and bEndocrine Unit, Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Vic., Australia
                Article
                68528 Nephron Physiol 2003;93:p51–p60
                10.1159/000068528
                12629271
                © 2003 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: 5, Tables: 2, References: 39, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/68528
                Categories
                Original Paper

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