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

YouFei Guan^1, 2, Chuanming Hao^1, 2, Dae Ryong Cha^1, 2, Reena Rao^1, 2, Wendell Lu^1, 2, Donald E Kohan^1, 3, 4, Mark A Magnuson^2, 5, Reyadh Redha^1, 2, Yahua Zhang^1, 2 & Matthew D Breyer^{1, 2, 4, 5}

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

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

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

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

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

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- (PPAR, 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 Pparg ^flox/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 ENaC) expression through a PPAR-dependent pathway. These studies identify Scnn1g as a PPAR target gene in the collecting duct. Activation of this pathway mediates fluid retention associated with TZDs, and suggests amiloride might provide a specific therapy.

	Top