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      Biochemical Renal Manifestations Induced by Consecutive Administration of Gentamicin in Rats

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          Abstract

          In the present study, we investigated the generation of lipid peroxides and changes in total phospholipid levels in the kidney tissue of rats with acquired resistance to gentamicin (GM). GM resistance was induced in Sprague-Dawley male rats by subcutaneously administering each rat a dose of 80 mg/kg/day of GM for 40 consecutive days. Twelve days after the GM administration, serum urea nitrogen peaked at 35 mg/dl. The urinary creatinine excretion progressively decreased, beginning 4 days after the start of GM administration. The fractional excretion of sodium progressively increased, beginning 4 days after the start of GM administration, peaking on the 10th day. However, despite the continuation of GM administration, the urinary creatinine excretion gradually increased, and the serum urea nitrogen concentrations recovered to previous levels after 21 days. We also analyzed the relationship between the acquired resistance to GM and changes in the reduced glutathione content and glutathione peroxidase activity. Simultaneously, we investigated sequential changes in the activities of phospholipase A<sub>2</sub> and phospholipase C, which release peroxidized membrane phospholipids into the cytoplasm via hydrolysis, as well as the relationship between changes in the kidney tissue phospholipid composition (sphingomyelin/phosphatidylcholine ratio) and renal function. We found that (1) the kidney tissue glutathione content rapidly decreased after GM administration before subsequently increasing and being maintained at a higher level; (2) the glutathione peroxidase activity showed a persistent decrease after GM administration; (3) the kidney tissue phospholipase A<sub>2</sub> activity decreased after GM administration, while the phospholipase C activity exhibited a sustained increase from 21 days, and (4) the spingomyelin/phosphatidylcholine ratio decreased on the 4th day before stabilizing when acquired resistance was obtained. Based on these findings, we conclude that an increased supply of reduced glutathione and the induction of an antioxidase, substituting for glutathione peroxidase, may play a significant role in the acquisition of resistance to acute renal failure which occurs with continuous GM administration. Improved membrane fluidity, achieved by maintenance of the membrane phospholipid composition by increased phospholipase C activity, may be an additional factor contributing to the recovery of the renal function.

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          Most cited references 4

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          A simple fluorometric assay for lipoperoxide in blood plasma.

           K Yagi (1976)
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            Effect of gentamicin on lipid peroxidation in rat renal cortex.

            We examined the hypothesis that lipid peroxidation participates in the pathogenesis of aminoglycoside-induced nephrotoxicity. Male Sprague-Dawley rats were injected subcutaneously with gentamicin, 100 mg/kg per day, for 1-4 days. Twenty-four or forty-eight hours after the last injection the rats were killed and the renal cortex was processed for total phospholipids, malondialdehyde (MDA), phospholipid fatty acid composition, superoxide dismutase, catalase and glutathione. Gentamicin induced a significant increase in total renal cortical phospholipids which was evident after a single injection and by the third injection reached a plateau 17% above the baseline level. MDA, an end product of lipid peroxidation, increased from 0.674 +/- 0.021 nmole/mg protein in the control group to 0.931 +/- 0.053 nmole/mg protein (P less than 0.001) 48 hr after the fourth injection. As another index of lipid peroxidation, we determined the shift from polyunsaturated to saturated fatty acids of renal cortical phospholipids. By the second injection of gentamicin we detected a significant decline of arachidonic acid (20:4) present in phospholipid. By the fourth injection, arachidonic acid had fallen 48% below control and was accompanied by reciprocal increases of more saturated fatty acids including linoleic (18:2), oleic (18:1) and palmitic (16:0) acids. The number of double bonds per mole of fatty acid declined from a baseline value of 1.62 +/- 0.01 to 1.20 +/- 0.02 (P less than 0.001) by the fourth injection of drug. Superoxide dismutase showed no consistent alteration, whereas catalase activity (k) fell from the control value of 0.221 +/- 0.007 min to 0.155 +/- 0.009 min (P less than 0.01) by the third injection, where k is the first-order rate constant. Total and reduced glutathione declined after the fourth injection of gentamicin accompanied by a shift to oxidized glutathione with an increase in the ratio of oxidized to total glutathione. These data support the conclusion that accelerated lipid peroxidation occurs early in the course of gentamicin administration and raise the possibility that lipid peroxidation is a proximal event in the injury cascade of gentamicin nephrotoxicity.
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              Decrease in the fluidity of brush-border membrane vesicles induced by gentamicin a spin-labeling study

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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                1998
                November 1998
                02 November 1998
                : 80
                : 3
                : 331-339
                Affiliations
                1st Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan
                Article
                45194 Nephron 1998;80:331–339
                10.1159/000045194
                9807043
                © 1998 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: 7, Tables: 1, References: 30, Pages: 9
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/45194
                Categories
                Original Paper

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