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Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

  • Renal Function, Body Fluids
  • Published:
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Abstract

PPARγ-agonists enhance insulin sensitivity and improve glucose utilization in diabetic patients. Adverse effects of PPARγ-agonists include volume retention and edema formation. Recent observations pointed to the ability of PPARγ agonists to enhance transcription of the serum and glucocorticoid-inducible kinase SGK1, a kinase that is genomically upregulated by mineralocorticoids and stimulates various renal channels and transporters including the renal epithelial Na+ channel ENaC. SGK1 has been proposed to mediate the volume retention after treatment with PPARγ agonists. To test this hypothesis, food containing the PPARγ agonist pioglitazone (0.02%, i.e., approximately 25 mg/kg bw/day) was administered to gene-targeted mice lacking SGK1 (sgk1 −/−, n = 12) and their wild-type littermates (sgk1 +/+, n = 12). According to in situ hybridization, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence, treatment with pioglitazone significantly increased renal SGK1 mRNA and protein expression in sgk1 +/+ mice. The treatment increased body weight significantly in both, sgk1 +/+ mice (+2.2 ± 0.3 g) and sgk −/− mice (+1.3 ± 0.2 g), and decreased hematocrit significantly in sgk1 +/+ mice (−6.5 ± 1.0%) and sgk1 −/− mice (−3.1 ± 0.6%). Both effects were significantly (p < 0.05) more pronounced in sgk1 +/+ mice. According to Evans Blue distribution, pioglitazone increased plasma volume only in sgk1 +/+ mice (from 50.9 ± 3.9 to 63.7 ± 2.5 μl/g bw) but not in sgk −/− mice (from 46.8 ± 3.8 to 48.3 ± 5.2 μl/g bw). Pioglitazone decreased aldosterone plasma levels and blood pressure and increased leptin plasma levels in both genotypes. We conclude that SGK1 contributes to but does not fully account for the volume retention during treatment with the PPARγ agonist pioglitazone.

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Acknowledgments

This work was supported by grants from DFG and BMBF (D.K., F.L., K.A.). The assistance of Miriam Reutelshoefer and Stefan Soellner in the performance of immunofluorescence is acknowledged. We also thank Andrea Janessa and Gisela Heck for the PCR measurements. We gratefully acknowledge the valuable discussions with Volker Vallon.

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Authors and Affiliations

  1. Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany

    Ferruh Artunc, Diana Sandulache, Omaima Nasir, Krishna M. Boini & Florian Lang

  2. Department of Internal Medicine IV, University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany

    Ferruh Artunc, Björn Friedrich & Teut Risler

  3. Diabetes Research DA, Merck KGaA, Frankfurter Str. 250, 64271, Darmstadt, Germany

    Norbert Beier & Wolfgang Scholz

  4. Central Analytical R&D, ZD-A/ZFA, Merck KGaA, Frankfurter Str. 250, 64271, Darmstadt, Germany

    Edith Dicks & Sven Pötzsch

  5. Department of Molecular Pathology, University of Tübingen, Liebermeisterstr. 8, 72076, Tübingen, Germany

    Karin Klingel

  6. Department of Pathology, University of Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany

    Kerstin Amann

  7. Biology Department, Indiana University-Purdue University at Indianapolis, 723 West Michigan St., Indianapolis, IN, 46202, USA

    Bonnie L. Blazer-Yost

  8. Department of Biology, Chemistry, and Pharmacy, Free University Berlin, Takusstr. 9, 14195, Berlin, Germany

    Dietmar Kuhl

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  1. Ferruh Artunc
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Artunc, F., Sandulache, D., Nasir, O. et al. Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone. Pflugers Arch - Eur J Physiol 456, 425–436 (2008). https://doi.org/10.1007/s00424-007-0401-5

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