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

研究成果: Article

23 引用 (Scopus)

抄録

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.

元の言語English
記事番号e00337-17
ジャーナルMolecular and Cellular Biology
37
発行部数24
DOI
出版物ステータスPublished - 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

これを引用

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. :: Molecular and Cellular Biology. 2017 ; 巻 37, 番号 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.",
author = "Yu Ishimoto and Reiko Inagi and Daisuke Yoshihara and Masanori Kugita and Shizuko Nagao and Akira Shimizu and Norihiko Takeda and Masaki Wake and Kenjiro Honda and Jing Zhou and Masaomi Nangaku",
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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, 巻. 37, 番号 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.

:: Molecular and Cellular Biology, 巻 37, 番号 24, e00337-17, 01.12.2017.

研究成果: Article

TY - JOUR

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

PY - 2017/12/1

Y1 - 2017/12/1

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.

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 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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