期刊
ONCOTARGET
卷 7, 期 11, 页码 12150-12162出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7859
关键词
PGC-1 alpha; podocytes; aldosterone; mitochondria; podocyte loss; Pathology Section
资金
- National Basic Research Program of China [2012CB517602]
- National Natural Science Foundation of China [81530023, 81325004, 81270797, 81270785]
- Natural Science Foundation of Jiangsu Province [BL2014007]
Growing evidence has shown that podocyte number is a critical determinant for the development of glomerulosclerosis and progressive renal failure. We previously reported that mitochondrial dysfunction (MtD) is an early event in podocyte injury. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is an important modulator of mitochondrial biogenesis. Here, we investigated the role of PGC-1 alpha overexpression in podocyte depletion and the involvement of mitochondria in this process. Following chronic aldosterone (Aldo) infusion for 14 days, we observed a remarkable podocyte loss, podocyte phenotypic changes, and albuminuria in WT mice. However, all these abnormalities were significantly attenuated in PGC-1 alpha transgenic mice. Next, we examined mitochondrial function in both genotypes with or without Aldo infusion. As expected, Aldo-induced MtD in glomeruli was markedly improved in PGC-1 alpha transgenic mice. In vitro, Aldo induced podocyte detachment and phenotypic changes in line with MtD in dose-and time-dependent manners. Similarly, ethidium bromide, an inducer of MtD, mimicked Aldo effects on podocyte detachment and phenotypic alterations. Notably, overexpression of PGC-1 alpha in podocytes entirely reversed Aldo-induced podocyte detachment, phenotypic changes, and MtD. Taken together, these findings demonstrate that PGC-1 alpha protects against podocyte depletion and phenotypic changes possibly by maintaining normal mitochondrial function.
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