Mitochondrial dysfunction accounts for aldosterone-induced epithelial-to-mesenchymal transition of renal proximal tubular epithelial cells

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• 作者：Yanggang Yuan^a ; ^b ; ¹ ; Ying Chen^a ; ¹ ; Ping Zhang^a ; ^b ; ^{zhaihua@njmu.edu.cn} ; Songming Huang^a ; ^b ; Chunhua Zhu^a ; ^b ; Guixia Ding^a ; ^b ; Bicheng Liu^c ; Tianxin Yang^d ; Aihua Zhang^a ; ^b ;
• 关键词：Epithelial&ndash ; mesenchymal transition ; Mitochondrial dysfunction ; Oxidative stress ; Aldosterone ; Free radicals
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 期刊代码：105_08915849
• 类别：med
• 出版时间：1 July, 2012
• 卷：53
• 期：1
• 页码：30-43
• 文件大小：2250 K

摘要

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-纬 coactivator-1伪 (PGC-1伪), a major regulator of oxidative metabolism and mitochondrial function, prevents EMT by improving MtD. Aldo decreased PGC-1伪 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 伪-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伪 induced MtD and EMT, whereas overexpression of PGC-1伪 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伪, or the SIRT1 activator resveratrol restored Aldo-induced MtD and EMT by upregulating PGC-1伪. These findings, which implicate a role for MtD in EMT and suggest that SIRT1 and PGC-1伪 coordinate to improve mitochondrial function and EMT, may guide us in therapeutic strategies for renal tubulointerstitial fibrosis.