Journal
KIDNEY INTERNATIONAL
Volume 82, Issue 7, Pages 771-789Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ki.2012.188
Keywords
aldosterone; mitochondrial dysfunction; PGC-1 alpha; podocytes; SIRT1
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Funding
- National Basic Research Program of China 973 Program [2012CB517600, 2012CB517602]
- National Natural Science Foundation of China [30872803, 30971376]
- Natural Science Foundation of Jiangsu Province [BK2009046]
- Specialized Research Fund for the Doctoral Program of Higher Education of China, State Education Ministry of China [20103234110006]
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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-gamma coactivator 1 alpha (PGC-1 alpha), affects podocyte damage. Aldosterone-induced injury decreased PGC-1 alpha expression, and induced mitochondrial and podocyte damage in dose- and time-dependent manners. The suppression of endogenous PGC-1 alpha 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-1 alpha, prevented aldosterone-induced mitochondrial damage and podocyte injury by upregulating PGC-1 alpha 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-1 alpha 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-1 alpha expression and, consequently, podocyte integrity. Kidney International (2012) 82, 771-789; doi:10.1038/ki.2012.188; published online 30 May 2012
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