Thiazolidinediones expand body fluid volume through PPARγ 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-γ (PPARγ, encoded by Pparg ), is most abundant in the collecti...
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Veröffentlicht in: | Nature medicine 2005-08, Vol.11 (8), p.861-866 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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
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 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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ISSN: | 1078-8956 1546-170X |
DOI: | 10.1038/nm1278 |