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Am J Physiol Renal Physiol (June 27, 2007). doi:10.1152/ajprenal.00480.2006
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Submitted on December 5, 2006
Accepted on May 11, 2007

Aldosterone induces epithelial-mesenchymal transition via ROS of mitochondrial origin

Aihua Zhang1, Zhanjun Jia1, Xiaohua Guo1, and Tianxin Yang1*

1 Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, United States

* To whom correspondence should be addressed. E-mail: tianxin.yang{at}hsc.utah.edu.

Aldosterone (Aldo) plays a direct profibrotic role in the kidney but the underlying mechanism is unclear. We examined the role of Aldo in epithelial-mesenchymal transition (EMT) both in vitro and in vivo. Exposure of human renal proximal tubular cells (HK-2) to Aldo for 48 hours induced EMT as evidenced by conversion to the spindle-like morphology, loss of E-cadherin, and de novo expression of {alpha}-SMA. The EMT was completely blocked by the selective mineralocorticoid receptor (MR) antagonist eplerenone. Aldo time-dependently increased intracellular reactive oxygen species (ROS) production that was detectable at 15 min and peaked (2.3-fold) at 60 min, as assessed by 2',7'-dichlorofluorescin diacetate fluorescence. Aldo-induced oxidative stress and EMT were both abolished by the mitochondrial respiratory chain complex I inhibitor rotenone, but not the NADPH oxidase inhibitor apocynin. Aldo induced phosphorylation of ERK1/2 that was completely blocked by rotenone. Male 129-C57/BL6 mice were treated with deoxycorticosterone acetate (DOCA)/salt for 3 weeks and animals were treated with vehicle or rotenone (600 ppm in diet) for the last wk. DOCA-salt induced a 2.5-fold increase in {alpha}-SMA and a 30% reduction of E-cadherin, as assessed by real time RT-PCR, that were both restricted to renal epithelial cells, as determined by immunohistochemistry. In contrast, DOCA-salt-induced changes in {alpha}-SMA and E-cadherin were completely blocked by treatment with rotenone. These observations suggest that aldosterone induces EMT via MR-mediated, mitochondrial originated-ROS-dependent ERK1/2 activation in renal tubular epithelial cells.




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[Abstract] [Full Text] [PDF]




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