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Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption

Nature Medicine volume 11, pages 861–866 (2005)Cite this article

Abstract

Thiazolidinediones (TZDs) are widely used to treat type 2 diabetes mellitus; however, their use is complicated by systemic fluid retention. Along the nephron, the pharmacological target of TZDs, peroxisome proliferator-activated receptor-γ (PPARγ, encoded by Pparg), is most abundant in the collecting duct. Here we show that mice treated with TZDs experience early weight gain from increased total body water. Weight gain was blocked by the collecting duct–specific diuretic amiloride and was also prevented by deletion of Pparg from the collecting duct, using Ppargflox/flox mice. Deletion of collecting duct Pparg decreased renal Na+ avidity and increased plasma aldosterone. Treating cultured collecting ducts with TZDs increased amiloride-sensitive Na+ absorption and Scnn1g mRNA (encoding the epithelial Na+ channel ENaCγ) expression through a PPARγ-dependent pathway. These studies identify Scnn1g as a PPARγ target gene in the collecting duct. Activation of this pathway mediates fluid retention associated with TZDs, and suggests amiloride might provide a specific therapy.

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Figure 1: Effects of TZDs on wild-type mice.
Figure 2: Characterization of AQP2-Cre × Ppargflox/flox versus wild-type mice.
Figure 3: Effect of pioglitazone on 22Na flux in cultured IMCDs.
Figure 4: Pioglitazone stimulates Scnn1g mRNA.

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Acknowledgements

We thank R. Zent for his critical reading of this manuscript and his comments. These studies were supported by the National Institute of Diabetes & Digestive & Kidney Disease grants DK37097 (to M.D.B.) and DK38226 (to J. Capdevila and M.D.B.), a US National Institutes of Health RO1 DK65074-01 to Y.G., an American Heart Association grant 160200B (to Y.G.) and a Genzyme renal innovative Award (to Y.G.). NMR fat determinations were performed through the Vanderbilt Mouse Metabolic Phenotyping Center (grant DK59637).

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Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, 21st Avenue South at Garland Avenue, Nashville, 37232, Tennessee, USA

    YouFei Guan, Chuanming Hao, Dae Ryong Cha, Reena Rao, Wendell Lu, Donald E Kohan, Reyadh Redha, Yahua Zhang & Matthew D Breyer

  2. S3223 MCN Vanderbilt University School of Medicine, 21st Avenue South at Garland Avenue, Nashville, 37232, Tennessee, USA

    YouFei Guan, Chuanming Hao, Dae Ryong Cha, Reena Rao, Wendell Lu, Mark A Magnuson, Reyadh Redha, Yahua Zhang & Matthew D Breyer

  3. Department of Nephrology, School of Medicine, University of Utah Medical Center, 50 North Medical Drive, Salt Lake City, 84132-2412, Utah, USA

    Donald E Kohan

  4. Veterans Affairs Medical Center, 1310 24th Avenue South, Nashville, 37212, Tennessee, USA

    Donald E Kohan & Matthew D Breyer

  5. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 21st Avenue South at Garland Avenue, Nashville, 37232, Tennessee, USA

    Mark A Magnuson & Matthew D Breyer

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Supplementary information

Supplementary Fig. 1

Location of candidate PPREs in mouse ENaCγ intron 1 sequence. (PDF 63 kb)

Supplementary Table 1

Length, weight and serum chemistries for AQP2Cre × Ppargflox/flox mice and Pparg wild-type mice (wt). (PDF 72 kb)

Supplementary Table 2

Electrophysiologic characterization and ion transport rates of Transwell® culture mouse IMCD cell monolayers. (PDF 55 kb)

Supplementary Table 3

Sequences used to search TESS for PPREs in mouse Scnn1 genes. (PDF 69 kb)

Supplementary Methods (PDF 178 kb)

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Guan, Y., Hao, C., Cha, D. et al. Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption. Nat Med 11, 861–866 (2005). https://doi.org/10.1038/nm1278

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