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

You Fei Guan, Chuanming Hao, Dae-Ryong Cha, Reena Rao, Wendell Lu, Donald E. Kohan, Mark A. Magnuson, Reyadh Redha, Yahua Zhang, Matthew D. Breyer

Research output: Contribution to journalArticle

476 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)861-866
Number of pages6
JournalNature Medicine
Volume11
Issue number8
DOIs
Publication statusPublished - 2005 Aug 1
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Guan, Y. F., Hao, C., Cha, D-R., Rao, R., Lu, W., Kohan, D. E., Magnuson, M. A., Redha, R., Zhang, Y., & Breyer, M. D. (2005). Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption. Nature Medicine, 11(8), 861-866. https://doi.org/10.1038/nm1278