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Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction

Renal fibrosis is the common pathological feature in a variety of chronic kidney diseases. Aging is highly associated with the progression of renal fibrosis. Among several determinants, mitochondrial dysfunction plays an important role in aging. However, the underlying mechanisms of mitochondrial dy...

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Autores principales: Miao, Jinhua, Liu, Jiafeng, Niu, Jing, Zhang, Yunfang, Shen, Weiwei, Luo, Congwei, Liu, Yahong, Li, Chuanjiang, Li, Hongyan, Yang, Peiliang, Liu, Youhua, Hou, Fan Fan, Zhou, Lili
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718575/
https://www.ncbi.nlm.nih.gov/pubmed/31318148
http://dx.doi.org/10.1111/acel.13004
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author Miao, Jinhua
Liu, Jiafeng
Niu, Jing
Zhang, Yunfang
Shen, Weiwei
Luo, Congwei
Liu, Yahong
Li, Chuanjiang
Li, Hongyan
Yang, Peiliang
Liu, Youhua
Hou, Fan Fan
Zhou, Lili
author_facet Miao, Jinhua
Liu, Jiafeng
Niu, Jing
Zhang, Yunfang
Shen, Weiwei
Luo, Congwei
Liu, Yahong
Li, Chuanjiang
Li, Hongyan
Yang, Peiliang
Liu, Youhua
Hou, Fan Fan
Zhou, Lili
author_sort Miao, Jinhua
collection PubMed
description Renal fibrosis is the common pathological feature in a variety of chronic kidney diseases. Aging is highly associated with the progression of renal fibrosis. Among several determinants, mitochondrial dysfunction plays an important role in aging. However, the underlying mechanisms of mitochondrial dysfunction in age‐related renal fibrosis are not elucidated. Herein, we found that Wnt/β‐catenin signaling and renin–angiotensin system (RAS) activity were upregulated in aging kidneys. Concomitantly, mitochondrial mass and functions were impaired with aging. Ectopic expression of Klotho, an antagonist of endogenous Wnt/β‐catenin activity, abolished renal fibrosis in d‐galactose (d‐gal)‐induced accelerated aging mouse model and significantly protected renal mitochondrial functions by preserving mass and diminishing the production of reactive oxygen species. In an established aging mouse model, dickkopf 1, a more specific Wnt inhibitor, and the mitochondria‐targeted antioxidant mitoquinone restored mitochondrial mass and attenuated tubular senescence and renal fibrosis. In a human proximal tubular cell line (HKC‐8), ectopic expression of Wnt1 decreased biogenesis and induced dysfunction of mitochondria, and triggered cellular senescence. Moreover, d‐gal triggered the transduction of Wnt/β‐catenin signaling, which further activated angiotensin type 1 receptor (AT1), and then decreased the mitochondrial mass and increased cellular senescence in HKC‐8 cells and primary cultured renal tubular cells. These effects were inhibited by AT1 blocker of losartan. These results suggest inhibition of Wnt/β‐catenin signaling and the RAS could slow the onset of age‐related mitochondrial dysfunction and renal fibrosis. Taken together, our results indicate that Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction.
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spelling pubmed-67185752019-10-01 Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction Miao, Jinhua Liu, Jiafeng Niu, Jing Zhang, Yunfang Shen, Weiwei Luo, Congwei Liu, Yahong Li, Chuanjiang Li, Hongyan Yang, Peiliang Liu, Youhua Hou, Fan Fan Zhou, Lili Aging Cell Original Articles Renal fibrosis is the common pathological feature in a variety of chronic kidney diseases. Aging is highly associated with the progression of renal fibrosis. Among several determinants, mitochondrial dysfunction plays an important role in aging. However, the underlying mechanisms of mitochondrial dysfunction in age‐related renal fibrosis are not elucidated. Herein, we found that Wnt/β‐catenin signaling and renin–angiotensin system (RAS) activity were upregulated in aging kidneys. Concomitantly, mitochondrial mass and functions were impaired with aging. Ectopic expression of Klotho, an antagonist of endogenous Wnt/β‐catenin activity, abolished renal fibrosis in d‐galactose (d‐gal)‐induced accelerated aging mouse model and significantly protected renal mitochondrial functions by preserving mass and diminishing the production of reactive oxygen species. In an established aging mouse model, dickkopf 1, a more specific Wnt inhibitor, and the mitochondria‐targeted antioxidant mitoquinone restored mitochondrial mass and attenuated tubular senescence and renal fibrosis. In a human proximal tubular cell line (HKC‐8), ectopic expression of Wnt1 decreased biogenesis and induced dysfunction of mitochondria, and triggered cellular senescence. Moreover, d‐gal triggered the transduction of Wnt/β‐catenin signaling, which further activated angiotensin type 1 receptor (AT1), and then decreased the mitochondrial mass and increased cellular senescence in HKC‐8 cells and primary cultured renal tubular cells. These effects were inhibited by AT1 blocker of losartan. These results suggest inhibition of Wnt/β‐catenin signaling and the RAS could slow the onset of age‐related mitochondrial dysfunction and renal fibrosis. Taken together, our results indicate that Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction. John Wiley and Sons Inc. 2019-07-18 2019-10 /pmc/articles/PMC6718575/ /pubmed/31318148 http://dx.doi.org/10.1111/acel.13004 Text en © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Miao, Jinhua
Liu, Jiafeng
Niu, Jing
Zhang, Yunfang
Shen, Weiwei
Luo, Congwei
Liu, Yahong
Li, Chuanjiang
Li, Hongyan
Yang, Peiliang
Liu, Youhua
Hou, Fan Fan
Zhou, Lili
Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction
title Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction
title_full Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction
title_fullStr Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction
title_full_unstemmed Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction
title_short Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction
title_sort wnt/β‐catenin/ras signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718575/
https://www.ncbi.nlm.nih.gov/pubmed/31318148
http://dx.doi.org/10.1111/acel.13004
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