title: Dysfunction of the PGC-1α-mitochondria axis confers adriamycin-induced podocyte injury.
abstract: Adriamycin (ADR)-induced nephropathy in animals is an experimental analog of human focal segmental glomerulosclerosis, which presents as severe podocyte injury and massive proteinuria and has a poorly understood mechanism. The present study was designed to test the hypothesis that the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α-mitochondria axis is involved in ADR-induced podocyte injury. Using MPC5 immortalized mouse podocytes, ADR dose dependently induced downregulation of nephrin and podocin, cell apoptosis, and mitochondrial dysfunction based on the increase in mitochondrial ROS production, decrease in mitochondrial DNA copy number, and reduction of mitochondrial membrane potential and ATP content. Moreover, ADR treatment also remarkably reduced the expression of PGC-1α, an important regulator of mitochondrial biogenesis and function, in podocytes. Strikingly, PGC-1α overexpression markedly attenuated mitochondrial dysfunction, the reduction of nephrin and podocin, and the apoptotic response in podocytes after ADR treatment. Moreover, downregulation of PGC-1α and mitochondria disruption in podocytes were also observed in rat kidneys with ADR administration, suggesting that the PGC-1α-mitochondria axis is relevant to in vivo ADR-induced podocyte damage. Taken together, these novel findings suggest that dysfunction of the PGC-1α-mitochondria axis is highly involved in ADR-induced podocyte injury. Targeting PGC-1α may be a novel strategy for the treatment of ADR nephropathy and human focal segmental glomerulosclerosis.
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xuan
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and.
authors.forename: Ruochen
authors.initials: R
authors.lastname: Che
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Guixia
authors.initials: G
authors.lastname: Ding
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, 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 Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Bai
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; and Institute of Pediatrics, Nanjing Medical University, 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 Institute of Pediatrics, Nanjing Medical University, 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 Institute of Pediatrics, Nanjing Medical University, Nanjing, China zhaihua@njmu.edu.cn.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D023421:Models, Animal; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C113267:nephrin; D004317:Doxorubicin
keywords: adriamycin nephropathy; mitochondrial dysfunction; peroxisome proliferator-activated receptor-γ coactivator-1α; podocyte injury