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

doi:10.1038/nm1278

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 journal › Article › peer-review

517 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 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.

Original language	English
Pages (from-to)	861-866
Number of pages	6
Journal	Nature Medicine
Volume	11
Issue number	8
DOIs	https://doi.org/10.1038/nm1278
Publication status	Published - 2005 Aug
Externally published	Yes

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm1278

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@article{75d38380d26e46acaad24028d551d8a3,

title = "Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption",

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.",

author = "Guan, {You Fei} and Chuanming Hao and Cha, {Dae Ryong} and Reena Rao and Wendell Lu and Kohan, {Donald E.} and Magnuson, {Mark A.} and Reyadh Redha and Yahua Zhang and Breyer, {Matthew D.}",

note = "Funding Information: 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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doi = "10.1038/nm1278",

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T1 - Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption

AU - Guan, You Fei

AU - Hao, Chuanming

AU - Cha, Dae Ryong

AU - Rao, Reena

AU - Lu, Wendell

AU - Kohan, Donald E.

AU - Magnuson, Mark A.

AU - Redha, Reyadh

AU - Zhang, Yahua

AU - Breyer, Matthew D.

N1 - Funding Information: 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).

PY - 2005/8

Y1 - 2005/8

N2 - 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.

AB - 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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JO - Nature Medicine

JF - Nature Medicine

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ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

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