Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease

Yu Ishimoto, Reiko Inagi, Daisuke Yoshihara, Masanori Kugita, Shizuko Nagao, Akira Shimizu, Norihiko Takeda, Masaki Wake, Kenjiro Honda, Jing Zhou, Masaomi Nangaku

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 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 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 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.

Original languageEnglish
Article numbere00337-17
JournalMolecular and Cellular Biology
Volume37
Issue number24
DOIs
Publication statusPublished - 01-12-2017

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Autosomal Dominant Polycystic Kidney
Cysts
Mitochondria
Superoxides
Oxidative Stress
Epithelial Cells
Kidney
Mutation
Peroxisome Proliferator-Activated Receptors
Calcineurin
Kidney Diseases
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
Mitochondrial DNA
Ion Channels
Nitric Oxide Synthase
Reactive Oxygen Species
Phosphotransferases
Animal Models
Antioxidants

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Ishimoto, Yu ; Inagi, Reiko ; Yoshihara, Daisuke ; Kugita, Masanori ; Nagao, Shizuko ; Shimizu, Akira ; Takeda, Norihiko ; Wake, Masaki ; Honda, Kenjiro ; Zhou, Jing ; Nangaku, Masaomi. / Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease. In: Molecular and Cellular Biology. 2017 ; Vol. 37, No. 24.
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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 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 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 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.",
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Ishimoto, Y, Inagi, R, Yoshihara, D, Kugita, M, Nagao, S, Shimizu, A, Takeda, N, Wake, M, Honda, K, Zhou, J & Nangaku, M 2017, 'Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease', Molecular and Cellular Biology, vol. 37, no. 24, e00337-17. https://doi.org/10.1128/MCB.00337-17

Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease. / Ishimoto, Yu; Inagi, Reiko; Yoshihara, Daisuke; Kugita, Masanori; Nagao, Shizuko; Shimizu, Akira; Takeda, Norihiko; Wake, Masaki; Honda, Kenjiro; Zhou, Jing; Nangaku, Masaomi.

In: Molecular and Cellular Biology, Vol. 37, No. 24, e00337-17, 01.12.2017.

Research output: Contribution to journalArticle

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T1 - Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease

AU - Ishimoto, Yu

AU - Inagi, Reiko

AU - Yoshihara, Daisuke

AU - Kugita, Masanori

AU - Nagao, Shizuko

AU - Shimizu, Akira

AU - Takeda, Norihiko

AU - Wake, Masaki

AU - Honda, Kenjiro

AU - Zhou, Jing

AU - Nangaku, Masaomi

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N2 - 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 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 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.

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