+1 Recommend
1 collections
      Call for Papers in Kidney and Blood Pressure ResearchKidney Function and Omics Science

      Submission Deadline: December 20, 2023

      Submit now

      • Record: found
      • Abstract: found
      • Article: found

      Rosiglitazone Regulates ENaC and Na-K-2Cl Cotransporter (NKCC 2) Abundance in the Obese Zucker Rat


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Background/Aims: Progressive diabetes is associated renal remodeling, which we previously showed correlated to reduced protein abundance of several major renal sodium transporters and channel subunits in the obese Zucker rat. Here we test whether rosiglitazone (RGZ), a peroxisome proliferator-activated subtype γ receptor agonist, would be protective and attenuate these changes. Methods: Male, obese and lean Zucker rats (9 weeks old) were randomly divided (n = 6/group) to receive control diet with or without RGZ at 3 mg/kg·bw/day for 12 weeks. Results: RGZ normalized blood glucose and plasma fructosamine levels in obese rats. Obese control rats had relatively increased fractional excretion of sodium (FE<sub>Na</sub>, sodium excretion relative to creatinine). Nonetheless, both obese and RGZ-treated rats had relatively higher 24-hour net sodium balances. Immunoblotting revealed obese rats had significantly reduced renal cortical protein abundances of the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC<sub>2</sub>) and the sodium hydrogen exchanger (NHE<sub>3</sub>). RGZ normalized NKCC<sub>2</sub> abundance and increased the abundance of the α-subunit of the epithelial sodium channel (ENaC). In contrast, in the outer medulla, obese rats had increased abundance of NKCC<sub>2</sub>, γ-ENaC (85-kDa), and endothelial NOS. Furthermore, RGZ caused a decrease in the abundance of cortical β- and γ-ENaC (85-kDa). Finally, the whole kidney abundances of α-1 Na-K-ATPase, α- β-, and γ-ENaC (70-kDa band) positively correlated with net sodium balance, whereas NKCC<sub>2</sub> was negatively correlated to FE<sub>Na</sub>. Conclusion: Chronic RGZ treatment of obese Zucker rats may preserve renal sodium reabsorptive capacity by its indirect actions to attenuate hyperglycemia as well as direct effects on transporter abundance and activity.

          Related collections

          Most cited references27

          • Record: found
          • Abstract: found
          • Article: not found

          Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney.

          Aldosterone stimulates sodium transport in the renal collecting duct by activating the epithelial sodium channel (ENaC). To investigate the basis of this effect, we have developed a novel set of rabbit polyclonal antibodies to the 3 subunits of ENaC and have determined the abundance and distribution of ENaC subunits in the principal cells of the rat renal collecting duct. Elevated circulating aldosterone (due to either dietary NaCl restriction or aldosterone infusion) markedly increased the abundance of alphaENaC protein without increasing the abundance of the beta and gamma subunits. Thus, alphaENaC is selectively induced by aldosterone. In addition, immunofluorescence immunolocalization showed a striking redistribution in ENaC labeling to the apical region of the collecting duct principal cells. Finally, aldosterone induced a shift in molecular weight of gammaENaC from 85 kDa to 70 kDa, consistent with physiological proteolytic clipping of the extracellular loop as postulated previously. Thus, at the protein level, the response of ENaC to aldosterone stimulation is heterogenous, with both quantitative and qualitative changes that can explain observed increases in ENaC-mediated sodium transport.
            • Record: found
            • Abstract: found
            • Article: not found

            Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention.

            The peroxisome proliferator-activated receptor subtype gamma (PPARgamma) ligands, namely the synthetic insulin-sensitizing thiazolidinedione (TZD) compounds, have demonstrated great potential in the treatment of type II diabetes. However, their clinical applicability is limited by a common and serious side effect of edema. To address the mechanism of TZD-induced edema, we generated mice with collecting duct (CD)-specific disruption of the PPARgamma gene. We found that mice with CD knockout of this receptor were resistant to the rosiglitazone- (RGZ) induced increases in body weight and plasma volume expansion found in control mice expressing PPARgamma in the CD. RGZ reduced urinary sodium excretion in control and not in conditional knockout mice. Furthermore, RGZ stimulated sodium transport in primary cultures of CD cells expressing PPARgamma and not in cells lacking this receptor. These findings demonstrate a PPARgamma-dependent pathway in regulation of sodium transport in the CD that underlies TZD-induced fluid retention.
              • Record: found
              • Abstract: found
              • Article: not found

              The heterotetrameric architecture of the epithelial sodium channel (ENaC).

              The epithelial sodium channel (ENaC) is a key element for the maintenance of sodium balance and the regulation of blood pressure. Three homologous ENaC subunits (alpha, beta and gamma) assemble to form a highly Na+-selective channel. However, the subunit stoichiometry of ENaC has not yet been solved. Quantitative analysis of cell surface expression of ENaC alpha, beta and gamma subunits shows that they assemble according to a fixed stoichiometry, with alpha ENaC as the most abundant subunit. Functional assays based on differential sensitivities to channel blockers elicited by mutations tagging each alpha, beta and gamma subunit are consistent with a four subunit stoichiometry composed of two alpha, one beta and one gamma. Expression of concatameric cDNA constructs made of different combinations of ENaC subunits confirmed the four subunit channel stoichiometry and showed that the arrangement of the subunits around the channel pore consists of two alpha subunits separated by beta and gamma subunits.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                July 2006
                19 July 2006
                : 26
                : 3
                : 245-257
                aDepartment of Medicine, Division of Endocrinology and Metabolism, bCenter for the Study of Sex Differences in Health and Disease, Georgetown University, Washington, D.C., USA
                93783 Am J Nephrol 2006;26:245–257
                © 2006 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.

                : 24 January 2006
                : 26 April 2006
                Page count
                Figures: 10, Tables: 1, References: 42, Pages: 13
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/93783
                Self URI (text/html): https://www.karger.com/Article/FullText/93783
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Report: Laboratory Investigation

                Cardiovascular Medicine,Nephrology
                Type 2 diabetes,BSC1 ,Endothelial NOS,Insulin resistance
                Cardiovascular Medicine, Nephrology
                Type 2 diabetes, BSC1 , Endothelial NOS, Insulin resistance


                Comment on this article