Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis

被引：253

作者：

Takiar, Vinita ^{[1
]}

Nishio, Saori ^{[2
]}

Seo-Mayer, Patricia ^{[1
]}

King, J. Darwin, Jr. ^{[3
,4
]}

Li, Hui ^{[3
,4
]}

Zhang, Li ^{[1
]}

Karihaloo, Anil ^{[2
]}

Hallows, Kenneth R. ^{[3
,4
]}

Somlo, Stefan ^{[2
]}

Caplan, Michael J. ^{[1
]}

机构：

[1] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA

[2] Yale Univ, Sch Med, Dept Med, Nephrol Sect, New Haven, CT 06520 USA

[3] Univ Pittsburgh, Sch Med, Renal Electrolyte Div, Dept Med, Pittsburgh, PA 15261 USA

[4] Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA 15261 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2011年 / 108卷 / 06期

基金：

美国国家卫生研究院;

关键词：

POLYCYSTIC KIDNEY-DISEASE; TRANSMEMBRANE CONDUCTANCE REGULATOR; CYSTIC-FIBROSIS; EPITHELIAL-CELLS; FLUID SECRETION; CELLULAR-ENERGY; CFTR INHIBITORS; METFORMIN; GROWTH; EXPRESSION;

D O I：

10.1073/pnas.1011498108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves both fluid secretion and abnormal proliferation of cyst-lining epithelial cells. The chloride channel of the cystic fibrosis transmembrane conductance regulator (CFTR) participates in secretion of cyst fluid, and the mammalian target of rapamycin (mTOR) pathway may drive proliferation of cyst epithelial cells. CFTR and mTOR are both negatively regulated by AMP-activated protein kinase (AMPK). Metformin, a drug in wide clinical use, is a pharmacological activator of AMPK. We find that metformin stimulates AMPK, resulting in inhibition of both CFTR and the mTOR pathways. Metformin induces significant arrest of cystic growth in both in vitro and ex vivo models of renal cystogenesis. In addition, metformin administration produces a significant decrease in the cystic index in two mouse models of ADPKD. Our results suggest a possible role for AMPK activation in slowing renal cystogenesis as well as the potential for therapeutic application of metformin in the context of ADPKD.

引用

页码：2462 / 2467

页数：6

共 48 条

[1] AMPK controls epithelial Na+ channels through Nedd4-2 and causes an epithelial phenotype when mutated [J].