期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 306, 期 12, 页码 F1410-F1417出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00622.2013
关键词
podocyte injury; mitochondrial dysfunction; adriamycin nephropathy; peroxisome proliferator-activated receptor-gamma coactivator-1 alpha
资金
- National Basic Research Program of China 973 Program [2012CB517602, 2013CB530604]
- National Natural Science Foundation of China [81325004, 81270785, 81100484]
- Natural Science Foundation of Jiangsu Province [BK2012001]
- Program for New Century Excellent Talents in University [NCET-12-0738]
- Special Foundation for Young Scientists of Nanjing [QRX11204]
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-gamma coactivator (PGC)-1 alpha-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-1 alpha, an important regulator of mitochondrial biogenesis and function, in podocytes. Strikingly, PGC-1 alpha overexpression markedly attenuated mitochondrial dysfunction, the reduction of nephrin and podocin, and the apoptotic response in podocytes after ADR treatment. Moreover, downregulation of PGC-1 alpha and mitochondria disruption in podocytes were also observed in rat kidneys with ADR administration, suggesting that the PGC-1 alpha-mitochondria axis is relevant to in vivo ADR-induced podocyte damage. Taken together, these novel findings suggest that dysfunction of the PGC-1 alpha-mitochondria axis is highly involved in ADR-induced podocyte injury. Targeting PGC-1 alpha may be a novel strategy for the treatment of ADR nephropathy and human focal segmental glomerulosclerosis.
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