Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 37, Issue 24, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00337-17
Keywords
mitochondrial metabolism; polycystic kidney disease
Categories
Funding
- Japan Society for the Promotion of Science [25461207, 15KT0088, 16K15465, 24390213, 16K15464]
- Japanese Association of Dialysis Physicians (JADP) [2012-05]
- Kyowa Hakko Kirin Co. Ltd.
- U.S. National Institutes of Health [RO1DK099532, R37DK51050]
- U.S. Department of Defense [PR152162]
- Grants-in-Aid for Scientific Research [16K15464, 26111003, 15K09247, 15KT0088, 16K15465] Funding Source: KAKEN
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Autosomal dominant polycystic kidney disease (ADPKD) constitutes the most inherited kidney disease. Mutations in the PKD1 and PKD2 genes, encoding the polycystin 1 and polycystin 2 Ca2+ ion channels, respectively, result in tubular epithelial cell-derived renal cysts. Recent clinical studies demonstrate oxidative stress to be present early in ADPKD. Mitochondria comprise the primary reactive oxygen species source and also their main effector target; however, the pathophysiological role of mitochondria in ADPKD remains uncharacterized. To clarify this function, we examined the mitochondria of cyst-lining cells in ADPKD model mice (Ksp-Cre PKD1(flox/flox)) and rats (Han: SPRD Cy/+), demonstrating obvious tubular cell morphological abnormalities. Notably, the mitochondrial DNA copy number and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) expression were decreased in ADPKD model animal kidneys, with PGC-1 alpha expression inversely correlated with oxidative stress levels. Consistent with these findings, human ADPKD cyst-derived cells with heterozygous and homozygous PKD1 mutation exhibited morphological and functional abnormalities, including increased mitochondrial superoxide. Furthermore, PGC-1 alpha expression was suppressed by decreased intracellular Ca2+ levels via calcineurin, p38 mitogen-activated protein kinase (MAPK), and nitric oxide synthase deactivation. Moreover, the mitochondrion-specific antioxidant MitoQuinone (MitoQ) reduced intracellular superoxide and inhibited cyst epithelial cell proliferation through extracellular signal-related kinase/MAPK inactivation. Collectively, these results indicate that mitochondrial abnormalities facilitate cyst formation in ADPKD.
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