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      Proximal Tubular Injury Attenuates Outer Medullary Hypoxic Damage: Studies in Perfused Rat Kidneys

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          Abstract

          The straight segment (S3) of the proximal tubule is predominantly damaged during renal ischemia-reflow, whereas medullary thick ascending limbs (mTALs) are principally affected in other models of hypoxic acute tubular necrosis (ATN). Since the latter injury pattern largely depends on the extent of reabsorptive activity during hypoxic stress, we hypothesized that proximal tubular damage might attenuate downstream mTAL injury by means of diminished distal solute delivery for reabsorption. In isolated rat kidneys perfused for 90 min with oxygenated Krebs-Henseleit solution, mTAL necrosis developed in 75 ± 3% of tubules in the mid-inner stripe of the outer medulla. By contrast, S3 segments in the outer stripe were minimally affected, with tubular fragmentation involving some 5 ± 2% of tubules. In kidneys subjected in vivo to proximal tubular injury and subsequently used for isolated perfusion studies, the injury pattern was inverted: following 20 and 30 min ischemia and reflow for 24 h, S3 fragmentation rose to 18 ± 16% and 72 ± 13%, while mTAL damage was reduced to 33 ± 10 and 24 ± 8%, respectively. In kidneys subjected in vivo to D-serine S3 necrosis rose to 100%, while mTAL damage fell to 1 ± 1% (p < 0.001). Substantial S3 tubular collapse (involving approximately 30% of tubules) and inner stripe interstitial hemorrhage were also noted, exclusively in kidneys subjected to ischemia-reflow. Proximal tubular necrosis alone or in combination with collapse inversely correlated with mTAL necrosis (R = –0.51 and –0.72, respectively, p < 0.003). This cogent inverse association might imply that disruption of the proximal nephron attenuates downstream mTAL necrosis by a reduction of distal tubular reabsorptive workload.

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          Most cited references 3

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          Hypoxia of the renal medulla--its implications for disease.

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            S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control.

            A dynamic cycle exists in which haemoglobin is S-nitrosylated in the lung when red blood cells are oxygenated, and the NO group is released during arterial-venous transit. The vasoactivity of S-nitrosohaemoglobin is promoted by the erythrocytic export of S-nitrosothiols. These findings highlight newly discovered allosteric and electronic properties of haemoglobin that appear to be involved in the control of blood pressure and which may facilitate efficient delivery of oxygen to tissues. The role of S-nitrosohaemoglobin in the transduction of NO-related activities may have therapeutic applications.
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              Pathogenesis of Renal Failure in Rhabdomyolysis: The Role of Myoglobin

              Rhabdomyolysis causes renal dysfunction associated with renal vasoconstriction, tubular toxicity and luminal obstruction. There is now accumulating evidence that renal injury, caused by lipid peroxidation, is important in the pathogenesis of renal failure. The proposed central role of free iron in this process is examined. Current data have shown that the heme center of myoglobin can initiate lipid peroxidation and renal injury without invoking release of free iron, and this process is due to redox cycling of the heme group from ferrous to ferric and to ferryl oxidation states. Alkaline conditions prevent myoglobin-induced lipid peroxidation by stabilizing the reactive ferryl myoglobin complex. This review explores the evidence for each of these mechanisms.
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                Author and article information

                Journal
                EXN
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2002
                2002
                27 June 2002
                : 10
                : 4
                : 259-266
                Affiliations
                aDepartment of Medicine, Hadassah Hospital, Mt. Scopus and the Hebrew University Medical School, Jerusalem, Israel; bDepartment of Pathology, Beth-Israel-Deaconess Medical Center and Harvard Medical School, Boston,Mass.,USA
                Article
                63700 Exp Nephrol 2002;10:259–266
                10.1159/000063700
                12097829
                © 2002 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: 3, Tables: 3, References: 37, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/63700
                Categories
                Original Paper

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