Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease.

Abstract

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 PKD1flox/flox) and rats (Han:SPRD Cy/+), demonstrating obvious tubular cell morphological abnormalities. Notably, the mitochondrial DNA copy number and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) expression were decreased in ADPKD model animal kidneys, with PGC-1α 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-1α 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.

• Authors: Yu Ishimoto, Reiko Inagi, Daisuke Yoshihara, Masanori Kugita, Shizuko Nagao, Akira Shimizu, Norihiko Takeda, Masaki Wake, Kenjiro Honda, Jing Zhou, Masaomi Nangaku
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 37 Issue 24 (12 15 2017) ISSN: 1098-5549 [Electronic] United States
• PMID: 28993480 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2017 Ishimoto et al.

Chemical References

• TRPP Cation Channels
• polycystic kidney disease 1 protein
• polycystic kidney disease 2 protein
• Superoxides
• Nitric Oxide Synthase
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• Calcineurin
• Calcium

Topics

• Animals
• Calcineurin (metabolism)
• Calcium (metabolism)
• Cell Proliferation (physiology)
• Cells, Cultured
• Cysts (metabolism, pathology)
• Disease Models, Animal
• Epithelial Cells (metabolism, pathology)
• Extracellular Signal-Regulated MAP Kinases
• Humans
• Kidney (metabolism, pathology)
• Mice
• Mitochondria (metabolism, pathology)
• Mutation (genetics)
• Nitric Oxide Synthase (metabolism)
• Polycystic Kidney, Autosomal Dominant (metabolism, pathology)
• Rats
• Signal Transduction (physiology)
• Superoxides (metabolism)
• TRPP Cation Channels (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)