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      L-Arginine Does Not Affect Renal Morphology and Cell Survival in Ischemic Acute Renal Failure in Rats

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          Abstract

          Background: L-Arginine ( L-Arg), a substrate of nitric oxide synthases, improves renal function in ischemic acute renal failure (iARF). We evaluated whether L-Arg improves renal morphology and cell survival in the course of iARF. Methods and Results: iARF was induced in rats by bilateral clamping of renal arteries for 45 min. L-Arg was applied intraperitoneally during clamping, and orally during 14 days of follow-up. Morphology and cell survival of renal cortical and medullar tissue was analyzed on days 1, 3, 7, and 14 of follow-up, using toluidine blue staining and immunohistochemistry of perfusion-fixated tissue, and Western blot analysis of tissue homogenate. Renal tubular injury showed typical features of necrosis and was most severe on days 1 and 3 after clamping, predominantly in S3 segments, with almost complete recovery by day 14. Enhanced medullar monocyte infiltration, determined by ED-1 expression as well as by immunohistochemistry, and enhanced expression of proliferating cell nuclear antigen (PCNA), indicative of proliferation and regeneration, accompanied these morphological changes. Compared to controls, L-Arg had no impact on renal morphology, ED-1, and PCNA expression. Furthermore, expression of markers of apoptosis Bcl-2, Bax, and cleaved caspase-3 was only slightly increased in iARF rats, compared to sham-operated animals, and was also not influenced by L-Arg. Conclusion: Despite its repeatedly reported positive impact on renal function as also shown in our model, L-Arg does not alter cell death and proliferation in the course of iARF in our model. Thus, different mechanisms have to be considered, in particular improved intrarenal hemodynamics.

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          Most cited references 13

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          Nitric oxide synthase in macula densa regulates glomerular capillary pressure.

           C Wilcox,  W Welch,  F Murad (1992)
          Tubular-fluid reabsorption by specialized cells of the nephron at the junction of the ascending limb of the loop of Henle and the distal convoluted tubule, termed the macula densa, releases compounds causing vasoconstriction of the adjacent afferent arteriole. Activation of this tubuloglomerular feedback response reduces glomerular capillary pressure of the nephron and, hence, the glomerular filtration rate. The tubuloglomerular feedback response functions in a negative-feedback mode to relate glomerular capillary pressure to tubular-fluid delivery and reabsorption. This system has been implicated in renal autoregulation, renin release, and longterm body fluid and blood-pressure homeostasis. Here we report that arginine-derived nitric oxide, generated in the macula densa, is an additional intercellular signaling molecule that is released during tubular-fluid reabsorption and counters the vasoconstriction of the afferent arteriole. Antibody to rat cerebellar constitutive nitric oxide synthase stained rat macula densa cells specifically. Microperfusion of the macula densa segment of single nephrons with N omega-methyl-L-arginine (an inhibitor of nitric oxide synthase) or with pyocyanin (a lipid-soluble inhibitor of endothelium-derived relaxation factor) showed that generation of nitric oxide can vasodilate the afferent arteriole and increase glomerular capillary pressure; this effect was blocked by drugs that prevent tubular-fluid reabsorption. We conclude that nitric oxide synthase in macula densa cells is activated by tubular-fluid reabsorption and mediates a vasodilating component to the tubuloglomerular feedback response. These findings imply a role for arginine-derived nitric oxide in body fluid-volume and blood-pressure homeostasis, in addition to its established roles in modulation of vascular tone by the endothelium and in neurotransmission.
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            Ischemic damage and repair in the rat proximal tubule: differences among the S1, S2, and S3 segments.

            Rats were subjected to 25 min of unilateral renal artery occlusion and were studied at 5, 15, and 30 min and at 1, 2, 4, 8, 16, 24, and 48 hr following ischemia. The patterns of epithelial injury and repair in proximal tubule (PT) segments S1, S2, and S3 were followed, and associated changes in renal function were determined. We found that S1 and S2 cells alike are only reversibly injured and recover completely to normalcy within 4 hr, whereas S3 cells selectively undergo progressive cell injury and death and are exfoliated into tubular lumina. The necrotic S3 cells are replaced by mitotic division of survivor cells 24 to 48 hr following the ischemic insult. In addition, there was selective damage within tubular cells. Wiithin 5 min of blood reflow following ischemia, the majority of brush border microvilli (MV) in all three PT segments underwent coalescence by membrane fusion and thus were interiorized into the cytoplasm of PT cells. A minority of MV fragmented and were shed into PT lumina, but nephron obstruction by shed membranes was only mild and transient, unlike in the 1-hr ischemia model. Loss of MV reached a maximum of 15 min. By 30 min, MV began to reappear; by 2 hr, large numbers of MV had been regenerated; and by 4 hr, S1 and S2 cells appeared normal. The regenerative process included the luminal repositioning of previously interiorized MV membrane. MV regeneration occurred in S3 segments also, but before the process was complete, the cells developed features of irreversible cellular injury. Glomerular filtration rate (GFR) was 22% of control at 30 min of reflow, rose progressively to 55% of normal by 7 to 8 hr, and was normal at 24 hr. Single nephron filtration rate (SNGFR) was not significantly different from normal throughout. Proximal tubular sodium reabsorption was depressed and urinary sodium excretion increased at 30 min and at 2 to 3 hr, i.e., at times when MV alterations were prominent, but both were normal by 7 to 8 hr when MV in S1 and S2 cells had been fully reconstituted. Our major conclusions are: 1) There is differential susceptibility by cell type to ischemic injury in rat PT. 2) A rapid brush border loss/regeneration cycle occurs after ischemic injury. 3) Intact brush border may be required for normal sodium reabsorption by PT. Reasons for the GFR/SNGFR discrepancy are unclear, but tubular malfunction may partly explain the phenomenon.
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              The nature of renal cell injury.

              The main functional change in patients with acute renal failure (ARF) is a decrease in glomerular filtration rate (GFR). The virtual complete recovery of renal function in those patients who survive ARF, as well as the minimal renal histological abnormalities during ARF when the GFR is less than 10 ml/min, suggest that a major component of the renal tubular cell injury is sublethal or reversible. Experimental models of acute tubular necrosis frequently have placed the emphasis on irreversible proximal tubular cell death. The nature of the renal tubular cell injury in ischemic acute renal failure, however, includes not only cell death (necrosis or apoptosis) but also sublethal injury causing cell dysfunction. The role of intracellular calcium, the calcium-dependent enzymes calpain, phospholipase A2 and nitric oxide synthase (NOS), in the pathophophysiology of this renal tubular cell injury during hypoxia/ischemia is described. The effects of calpain and nitric oxide (NO) on the cytoskeleton and cell adhesion are discussed. Potential mechanisms whereby tubular injury leads to a profound fall in GFR, including increased tubuloglomerular feedback and increased distal tubular obstruction, in ischemic acute renal failure are proposed.
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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2005
                November 2005
                26 October 2005
                : 101
                : 3
                : p39-p50
                Affiliations
                Division of Nephrology, Department of Medicine, Julius Maximilian University, Würzburg, Germany
                Article
                86647 Nephron Physiol 2005;101:p39–p50
                10.1159/000086647
                15990449
                © 2005 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: 11, References: 24, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/86647
                Categories
                Original Paper

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