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Growing evidence suggests a pathogenic role of mitochondrial dysfunction in chronic kidney diseases. Therefore, the present study aimed to define the roles of mitochondria in proteinuria-induced renal tubular injury and their underlying mechanisms. Using the albumin-overload mouse model, we observed severe tubular structure damage and striking tubular cell apoptosis. Furthermore, tubular epithelial cells displayed a loss of E-cadherin expression and gained expression of \u03b1-smooth muscle actin and vimentin, indicating a cellular phenotypic alteration. Strikingly, these albumin overload-induced abnormalities were robustly blocked by a mitochondrial SOD2 mimic, Mn(III) tetrakis (4-benzoic acid)porphyrin chloride (MnTBAP). In agreement with these results, we observed a marked change in mitochondrial morphology accompanied by mitochondrial cytochrome c release and a copy number reduction of mitochondrial DNA. These alterations were largely reversed by MnTBAP, suggesting a key role for mitochondria-derived oxidative stress in mediating the albumin effect on mitochondrial dysfunction and subsequent tubular injury. Moreover, the NOD-like receptor family, pyrin domain-containing 3 (NLRP3)\/caspase-1\/cytokine cascade was activated in the kidney by albumin overload and was entirely abolished by MnTBAP. In albumin-treated mouse proximal tubular cells, albumin directly induced ROS production, mitochondrial dysfunction, NLRP3\/caspase-1\/cytokine cascade activation, cell apoptosis, and cellular phenotypic transition. Similar to our in vivo results, treatment with either MnTBAP or cyclosporin A, a mitochondrial permeability transition pore inhibitor, remarkably attenuated these abnormalities in cells. Taken together, these novel findings demonstrate a potential role for the mitochondrial dysfunction\/NLRP3 inflammasome axis in the pathogenesis of proteinuria-induced renal tubular injury.<\/jats:p>","DOI":"10.1152\/ajprenal.00203.2014","type":"journal-article","created":{"date-parts":[[2015,2,19]],"date-time":"2015-02-19T01:34:24Z","timestamp":1424309664000},"page":"F857-F866","source":"Crossref","is-referenced-by-count":79,"title":["Mitochondrial dysfunction confers albumin-induced NLRP3 inflammasome activation and renal tubular injury"],"prefix":"10.1152","volume":"308","author":[{"given":"Yibo","family":"Zhuang","sequence":"first","affiliation":[{"name":"Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and"},{"name":"Jiangsu Key Laboratory of Pediatrics, Nanjing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marchella","family":"Yasinta","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; 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