Activation of peroxisome proliferator-activated receptor-γ coactivator 1α ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury.
Glomerular podocytes are highly specialized epithelial cells whose injury in glomerular diseases causes proteinuria. Since mitochondrial dysfunction is an early event in podocyte injury, we tested whether a major regulator of oxidative metabolism and mitochondrial function, the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), affects podocyte damage. Aldosterone-induced injury decreased PGC-1α expression, and induced mitochondrial and podocyte damage in dose- and time-dependent manners. The suppression of endogenous PGC-1α by RNAi caused podocyte mitochondrial damage and apoptosis while its increase by infection with an adenoviral vector prevented aldosterone-induced mitochondrial malfunction and inhibited injury. Overexpression of the silent mating type information regulation 2 homolog 1, a gene upstream of PGC-1α, prevented aldosterone-induced mitochondrial damage and podocyte injury by upregulating PGC-1α at both the transcriptional and post-translational levels. Resveratrol, a SIRT1 activator, attenuated aldosterone-induced mitochondrial malfunction and podocyte injury in vitro and in aldosterone-infused mice in vivo. Hence, endogenous PGC-1α may be important for maintenance of mitochondrial function in podocytes under normal conditions. Activators of SIRT1, such as resveratol, may be therapeutically useful in glomerular diseases to promote and maintain PGC-1α expression and, consequently, podocyte integrity.
Department of Nephrology, Nanjing Children's Hospital, Institute of Pediatrics, Nanjing Medical University, Nanjing, China.
Yanggang
Y
Yuan
Songming
S
Huang
Wenyan
W
Wang
Yingying
Y
Wang
Ping
P
Zhang
Chunhua
C
Zhu
Guixia
G
Ding
Bicheng
B
Liu
Tianxin
T
Yang
Aihua
A
Zhang
D000450:Aldosterone; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D019610:Cytoprotection; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000472:pathogenicity; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014162:Transfection
D000451:Mineralocorticoid Receptor Antagonists; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D018161:Receptors, Mineralocorticoid; D013267:Stilbenes; D015534:Trans-Activators; D014157:Transcription Factors; D000450:Aldosterone; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol