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      Rosiglitazone Increases PPARγ in Renal Tubular Epithelial Cells and Protects against Damage by Hydrogen Peroxide

      American Journal of Nephrology
      S. Karger AG
      Cell damage, Rosiglitazone, PPARγ, Renal tubular cells, Oxidative stress

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          Background/Aims: Thiazolidinediones (TZD) are ligands known to bind to and activate the nuclear peroxisome proliferator-activated receptor γ (PPARγ), and are currently used as insulin sensitizers in type 2 diabetes. Recently, several studies have shown that TZD may have a role in renal protection in various experimental models. However, the precise mechanisms by which TZD may possibly affect tubular cell survival after injury remain unclear. We studied the influence of the TZD rosiglitazone on PPARγ expression and cell function with cellular damage induced by increasing hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) concentrations in bovine renal tubular epithelial cells (bEPC) to determine whether rosiglitazone is cytoprotective under these conditions. Methods: bEPC were cultured in the presence of H<sub>2</sub>O<sub>2</sub> after pretreatment with or without 25 µ M rosiglitazone. The expression of PPARγ mRNA and protein were determined using RT-PCR or Western blots, respectively, after 6 and 24 h. Some cells also received actinomycin D or cycloheximide and PPARγ protein expression was tested. Proliferation rates of cultures were compared after 15 h and after a recovery phase of 6 days. Apoptosis was assessed by DNA fragmentation. Nuclear PPARγ activity was evaluated by electrophoretic mobility shift assay (EMSA), and the cellular location was detected using immunofluorescence. Results: Incubation of bEPC with H<sub>2</sub>O<sub>2</sub> concentrations up to 0.75 m M did not induce apoptosis as tested by DNA fragmentation assay, but significantly and dose-dependently reduced proliferation 15 h after injury as measured by [<sup>3</sup>H]thymidine incorporation. 25 µ M rosiglitazone alone also reduced proliferation and failed to attenuate the H<sub>2</sub>O<sub>2</sub>-mediated inhibition of proliferation. However, rosiglitazone facilitates recovery of tubular cells 6 days after H<sub>2</sub>O<sub>2</sub>-induced injury. Rosiglitazone (25 µ M) increased PPARγ mRNA and protein expression in bEPC in the absence of H<sub>2</sub>O<sub>2</sub>. Rosiglitazone failed to increase PPARγ mRNA in cells with oxidative stress, but Western blots revealed an increase in cellular PPARγ protein content in the presence of rosiglitazone and increasing concentrations of H<sub>2</sub>O<sub>2</sub>. This increase in PPARγ protein content was almost totally abolished in the presence of 1 µg/ml cycloheximide, but was only marginally reduced by 0.1 µg/ml actinomycin D. EMSA showed a robust increase in nuclear PPARγ protein binding in vitro to its consensus site after rosiglitazone whereas H<sub>2</sub>O<sub>2</sub> treatment reduced PPARγ activation. Rosiglitazone treatment of cells with oxidative stress preserved nuclear transactivation of PPARγ. Conclusions: Rosiglitazone increases the PPARγ content in bEPC after H<sub>2</sub>O<sub>2</sub>-induced injury by a posttranscriptional mechanism. Activation of PPARγ facilitates the long-term recovery of tubular cells 6 days after oxidative injury, but had no effect on the attenuated proliferation shortly after injury. TZD cannot prevent oxidative injury to tubular cells, but may be important mediators to enhance cellular recovery after oxidative stress.

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          Most cited references30

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          Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb.

          Members of the Hedgehog (Hh) and Wnt/Wingless (Wg) families of secreted proteins control many aspects of growth and patterning during animal development. Hh signal transduction leads to increased stability of a transcription factor, Cubitus interruptus (Ci), whereas Wg signal transduction causes increased stability of Armadillo (Arm/beta-catenin), a possible co-factor for the transcriptional regulator Lef1/TCF. Here we describe a new gene, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways. Loss of function of slimb results in a cell-autonomous accumulation of high levels of both Ci and Arm, and the ectopic expression of both Hh- and Wg- responsive genes. The slimb gene encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway. We propose that Slimb protein normally targets Ci and Arm for processing or degradation by the ubiquitin/proteasome pathway, and that Hh and Wg regulate gene expression at least in part by inducing changes in Ci and Arm, which protect them from Slimb-mediated proteolysis.
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            Peroxisome proliferator-activated receptor gamma in diabetes and metabolism.

            The peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been the focus of intense research during the past decade because ligands for this receptor have emerged as potent insulin sensitizers used in the treatment of type 2 diabetes. Recent advances include the discovery of novel genes that are regulated by PPAR-gamma, which helps explain how activation of this adipocyte-predominant transcription factor regulates glucose and lipid homeostasis. Increased levels of circulating free fatty acids and lipid accumulation in non-adipose tissue have been implicated in the development of insulin resistance. This situation is improved by PPAR-gamma ligands, which promote fatty acid storage in fat depots and regulate the expression of adipocyte-secreted hormones that impact on glucose homeostasis. The net result of the pleiotropic effects of PPAR-gamma ligands is improvement of insulin sensitivity, although undesired side-effects limit the utility of this therapy. It might be possible to dissociate the anti-diabetic and adverse effects through selective modulation of PPAR-gamma activity.
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              Oxidants in chronic kidney disease.

              Chronic kidney disease is a worldwide public health problem that affects approximately 10% of the US adult population and is associated with a high prevalence of cardiovascular disease and high economic cost. Chronic renal insufficiency, once established, tends to progress to end-stage kidney disease, suggesting some common mechanisms for ultimately causing scarring and further nephron loss. This review defines the term reactive oxygen metabolites (ROM), or oxidants, and presents the available experimental evidence in support of the role of oxidants in diabetic and nondiabetic glomerular disease and their role in tubulointerstitial damage that accompanies progression. It concludes by reviewing the limited human data that provide some proof of concept that the observations in experimental models may be relevant to human disease.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                July 2007
                03 July 2007
                : 27
                : 4
                : 425-434
                Department of Internal Medicine III, University of Jena, Jena, Germany
                105125 Am J Nephrol 2007;27:425–434
                © 2007 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.

                : 26 March 2007
                : 03 June 2007
                Page count
                Figures: 9, References: 34, Pages: 10
                Original Report: Laboratory Investigation

                Cardiovascular Medicine,Nephrology
                Cell damage,Rosiglitazone,PPARγ,Renal tubular cells,Oxidative stress


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