title: Mitochondrial dysfunction accounts for aldosterone-induced epithelial-to-mesenchymal transition of renal proximal tubular epithelial cells.
abstract: 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-γ coactivator-1α (PGC-1α), a major regulator of oxidative metabolism and mitochondrial function, prevents EMT by improving MtD. Aldo decreased PGC-1α 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 α-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-1α induced MtD and EMT, whereas overexpression of PGC-1α prevented Aldo-induced MtD and inhibited EMT. Similarly, overexpression of silent mating type information regulation 2 homolog 1 (SIRT1), a gene upstream of PGC-1α, or the SIRT1 activator resveratrol restored Aldo-induced MtD and EMT by upregulating PGC-1α. These findings, which implicate a role for MtD in EMT and suggest that SIRT1 and PGC-1α coordinate to improve mitochondrial function and EMT, may guide us in therapeutic strategies for renal tubulointerstitial fibrosis.
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing 210029, China.
authors.forename: Yanggang
authors.initials: Y
authors.lastname: Yuan
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Songming
authors.initials: S
authors.lastname: Huang
authors.forename: Chunhua
authors.initials: C
authors.lastname: Zhu
authors.forename: Guixia
authors.initials: G
authors.lastname: Ding
authors.forename: Bicheng
authors.initials: B
authors.lastname: Liu
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055765:Shc Signaling Adaptor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D015820:Cadherins; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C499631:TFAM protein, human; D014157:Transcription Factors; D000450:Aldosterone; C447939:SIRT1 protein, human; D056564:Sirtuin 1