title: Mitochondrial dysfunction confers albumin-induced NLRP3 inflammasome activation and renal tubular injury.
abstract: Proteinuria is involved in the development of tubular lesions and in the progressive loss of renal function in chronic kidney diseases via uncertain mechanisms. 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 α-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.
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Jiangsu Key Laboratory of Pediatrics, Nanjing, China.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Jiangsu Key Laboratory of Pediatrics, Nanjing, China.
authors.forename: Marchella
authors.initials: M
authors.lastname: Yasinta
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Jiangsu Key Laboratory of Pediatrics, Nanjing, China.
authors.forename: Caiyu
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Jiangsu Key Laboratory of Pediatrics, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and.
authors.forename: Guixia
authors.initials: G
authors.lastname: Ding
authors.affiliation: Jiangsu Key Laboratory of Pediatrics, Nanjing, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Bai
authors.affiliation: Jiangsu Key Laboratory of Pediatrics, Nanjing, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Pediatrics, Nanjing, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Ni
authors.affiliation: Jiangsu Key Laboratory of Pediatrics, Nanjing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Jiangsu Key Laboratory of Pediatrics, Nanjing, China.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Jiangsu Key Laboratory of Pediatrics, Nanjing, China.
authors.forename: Songming
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Jiangsu Key Laboratory of Pediatrics, Nanjing, China zhaihua@njmu.edu.cm.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000419:Albuminuria / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D019610:Cytoprotection; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D057507:Mice, 129 Strain; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018384:Oxidative Stress; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D008665:Metalloporphyrins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D016572:Cyclosporine
keywords: NOD-like receptor family, pyrin; domain-containing 3; mitochondria; proteinuria; renal tubular injury