Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption.
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-gamma (PPARgamma, 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 ENaCgamma) expression through a PPARgamma-dependent pathway. These studies identify Scnn1g as a PPARgamma target gene in the collecting duct. Activation of this pathway mediates fluid retention associated with TZDs, and suggests amiloride might provide a specific therapy.
Guan
YouFei
Y
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, 21st Avenue South at Garland Avenue, Nashville, Tennessee 37232, USA.
Hao
Chuanming
C
Cha
Dae Ryong
DR
Rao
Reena
R
Lu
Wendell
W
Kohan
Donald E
DE
Magnuson
Mark A
MA
Redha
Reyadh
R
Zhang
Yahua
Y
Breyer
Matthew D
MD
D000584:Amiloride / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001774:Blood Chemical Analysis; D001826:Body Fluids / Q000187:drug effects; D001835:Body Weight; D047369:Chromatin Immunoprecipitation; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D053503:Epithelial Sodium Channels; D018390:Gene Targeting; D051379:Mice; D008822:Mice, Transgenic; D009399:Nephrons / Q000187:drug effects / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology*; D014882:Water-Electrolyte Balance / Q000187:drug effects / Q000502:physiology*
D053503:Epithelial Sodium Channels; D047495:PPAR gamma; C507053:Scnn1g protein, mouse; D015222:Sodium Channels; D045162:Thiazolidinediones; D000584:Amiloride; D012964:Sodium