期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 53, 期 1, 页码 30-43出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2012.03.015
关键词
Epithelial-mesenchymal transition; Mitochondrial dysfunction; Oxidative stress; Aldosterone; Free radicals
资金
- National Basic Research Program of China 973, Program [2012CB517600, 2012CB517602]
- National Natural Science Foundation of China [30872803, 81070551]
- Natural Science Foundation of Jiangsu Province [BK2010122]
Epithelial-mesenchymal transition (EMT) plays a pivotal role in the pathogenesis of renal tubulointerstitial fibrosis. We previously demonstrated that aldosterone (Aldo)-induced EMT is dependent on mitochondrial-derived oxidative stress. This study investigated whether mitochondrial dysfunction (MtD) is involved in the pathogenesis of EMT and whether peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), a major regulator of oxidative metabolism and mitochondrial function, prevents EMT by improving MtD. Aldo decreased PGC-1 alpha expression while increasing its acetylation and induced MtD, as evidenced by oxidative stress, mitochondrial membrane potential collapse, mitochondrial DNA damage, and mitochondrial complex activity reduction. Aldo time-dependently induced p66Shc phosphorylation and expression. Mineralocorticoid receptor antagonist eplerenone and p66Shc short interfering RNA prevented Aldo-induced MtD and EMT, as evidenced by downregulation of alpha-smooth muscle actin and upregulation of E-cadherin. Mitochondrial DNA depletion by ethidium bromide or mitochondrial transcription factor A inhibitory RNA (RNAi) induced MtD, further promoting EMT. RNAi-mediated suppression of PGC-1 alpha induced MtD and EMT, whereas overexpression of PGC-1 alpha prevented Aldo-induced MtD and inhibited EMT. Similarly, overexpression of silent mating type information regulation 2 homolog 1 (SIRT1), a gene upstream of PGC-1 alpha, or the SIRT1 activator resveratrol restored Aldo-induced MtD and EMT by upregulating PGC-1 alpha. These findings, which implicate a role for MtD in EMT and suggest that SIRT1 and PGC-1 alpha coordinate to improve mitochondrial function and EMT, may guide us in therapeutic strategies for renal tubulointerstitial fibrosis. (c) 2012 Elsevier Inc. All rights reserved.
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