| First Author | Ishimoto Y | Year | 2017 |
| Journal | Mol Cell Biol | PubMed ID | 28993480 |
| Mgi Jnum | J:257362 | Mgi Id | MGI:6110735 |
| Doi | 10.1128/MCB.00337-17 | Citation | Ishimoto Y, et al. (2017) Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease. Mol Cell Biol |
| abstractText | Autosomal dominant polycystic kidney disease (ADPKD) constitutes the most common inherited kidney disease. Mutations in the PKD1 and PKD2 genes, encoding respective polycystin-1 and polycystin-2 Ca(2+) ion channels, results in tubular epithelial cell-derived renal cysts. Recent clinical studies demonstrate oxidative stress as 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, mitochondrial DNA copy number and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) expression were decreased in ADPKD model animal kidneys, with PGC-1alpha 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-1alpha expression was suppressed by decreased intracellular Ca(2+) levels via calcineurin, p38 mitogen-activated protein kinase (MAPK), and nitric oxide synthase deactivation. Moreover, the mitochondria-specific antioxidant MitoQ reduced intracellular superoxide and inhibited cyst epithelial-cell proliferation through extracellular signal-related kinase/MAPK inactivation. Collectively, these results indicated mitochondrial abnormalities facilitate cyst formation in ADPKD. |
