PMID- 28993480 OWN - NLM STAT- MEDLINE DCOM- 20190415 LR - 20191008 IS - 1098-5549 (Electronic) IS - 0270-7306 (Print) IS - 0270-7306 (Linking) VI - 37 IP - 24 DP - 2017 Dec 15 TI - Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease. LID - 10.1128/MCB.00337-17 [doi] LID - e00337-17 AB - 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 Ca(2+) 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 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 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. CI - Copyright (c) 2017 Ishimoto et al. FAU - Ishimoto, Yu AU - Ishimoto Y AD - Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan. AD - Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan. FAU - Inagi, Reiko AU - Inagi R AD - Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan inagi-npr@umin.ac.jp mnangaku-tky@umin.ac.jp. AD - Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan. FAU - Yoshihara, Daisuke AU - Yoshihara D AD - Education and Research Center of Animal Models for Human Diseases, Fujita Health University, Aichi, Japan. FAU - Kugita, Masanori AU - Kugita M AD - Education and Research Center of Animal Models for Human Diseases, Fujita Health University, Aichi, Japan. FAU - Nagao, Shizuko AU - Nagao S AD - Education and Research Center of Animal Models for Human Diseases, Fujita Health University, Aichi, Japan. FAU - Shimizu, Akira AU - Shimizu A AD - Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan. FAU - Takeda, Norihiko AU - Takeda N AD - Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan. FAU - Wake, Masaki AU - Wake M AD - Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan. FAU - Honda, Kenjiro AU - Honda K AD - Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan. FAU - Zhou, Jing AU - Zhou J AD - Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. FAU - Nangaku, Masaomi AU - Nangaku M AD - Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan inagi-npr@umin.ac.jp mnangaku-tky@umin.ac.jp. LA - eng GR - R01 DK099532/DK/NIDDK NIH HHS/United States GR - R37 DK051050/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20171128 PL - United States TA - Mol Cell Biol JT - Molecular and cellular biology JID - 8109087 RN - 0 (TRPP Cation Channels) RN - 0 (polycystic kidney disease 1 protein) RN - 0 (polycystic kidney disease 2 protein) RN - 11062-77-4 (Superoxides) RN - EC 1.14.13.39 (Nitric Oxide Synthase) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 3.1.3.16 (Calcineurin) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Calcineurin/metabolism MH - Calcium/metabolism MH - Cell Proliferation/physiology MH - Cells, Cultured MH - Cysts/metabolism/*pathology MH - Disease Models, Animal MH - Epithelial Cells/metabolism/pathology MH - Extracellular Signal-Regulated MAP Kinases MH - Humans MH - Kidney/metabolism/pathology MH - Mice MH - Mitochondria/metabolism/*pathology MH - Mutation/genetics MH - Nitric Oxide Synthase/metabolism MH - Polycystic Kidney, Autosomal Dominant/metabolism/*pathology MH - Rats MH - Signal Transduction/physiology MH - Superoxides/metabolism MH - TRPP Cation Channels/metabolism MH - p38 Mitogen-Activated Protein Kinases/metabolism PMC - PMC5705822 OTO - NOTNLM OT - mitochondrial metabolism OT - polycystic kidney disease EDAT- 2017/10/11 06:00 MHDA- 2019/04/16 06:00 PMCR- 2017/11/28 CRDT- 2017/10/11 06:00 PHST- 2017/06/21 00:00 [received] PHST- 2017/09/28 00:00 [accepted] PHST- 2017/10/11 06:00 [pubmed] PHST- 2019/04/16 06:00 [medline] PHST- 2017/10/11 06:00 [entrez] PHST- 2017/11/28 00:00 [pmc-release] AID - MCB.00337-17 [pii] AID - 00337-17 [pii] AID - 10.1128/MCB.00337-17 [doi] PST - epublish SO - Mol Cell Biol. 2017 Nov 28;37(24):e00337-17. doi: 10.1128/MCB.00337-17. Print 2017 Dec 15.