Tubular TMEM16A promotes tubulointerstitial fibrosis by suppressing PGC-1α-mediated mitochondrial homeostasis in diabetic kidney disease

Tubulointerstitial fibrosis (TIF) plays a crucial role in the progression of diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain obscure. The present study aimed to examine whether transmembrane member 16A (TMEM16A), a Ca 2+ -activated chloride channel, contributes to...

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Published in:Cellular and molecular life sciences : CMLS 2023-12, Vol.80 (12), p.347-347, Article 347
Main Authors: Ji, Jia-Ling, Li, Jun-Ying, Liang, Jian-Xiang, Zhou, Yan, Liu, Cong-Cong, Zhang, Yao, Zhang, Ai-Qing, Liu, Hong, Ma, Rui-Xia, Li, Zuo-Lin
Format: Article
Language:English
Subjects:
Animal models
Animals
Biochemistry
Biomedical and Life Sciences
Biomedicine
Calcium chloride
Calcium ions
Cell Biology
Channel gating
Chloride ions
Diabetes
Diabetes Mellitus
Diabetic Nephropathies - genetics
Diabetic nephropathy
Fibrosis
Homeostasis
Intracellular
Ion channels
Kidney diseases
Kidneys
Life Sciences
Mice
Mitochondria
Molecular modelling
Original
Original Article
therapeutics
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cited_by cdi_FETCH-LOGICAL-c464t-afe4db84137e1668cd0447431eedd30c281406fd3e65ee1255e6ad33818c5b6b3
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container_issue 12
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container_title Cellular and molecular life sciences : CMLS
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creator Ji, Jia-Ling
Li, Jun-Ying
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Zhang, Ai-Qing
Liu, Hong
Ma, Rui-Xia
Li, Zuo-Lin
description Tubulointerstitial fibrosis (TIF) plays a crucial role in the progression of diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain obscure. The present study aimed to examine whether transmembrane member 16A (TMEM16A), a Ca 2+ -activated chloride channel, contributes to the development of TIF in DKD. Interestingly, we found that TMEM16A expression was significantly up-regulated in tubule of murine model of DKD, which was associated with development of TIF. In vivo inhibition of TMEM16A channel activity with specific inhibitors Ani9 effectively protects against TIF. Then, we found that TMEM16A activation induces tubular mitochondrial dysfunction in in vivo and in vitro models, with the evidence of the TMEM16A inhibition with specific inhibitor. Mechanically, TMEM16A mediated tubular mitochondrial dysfunction through inhibiting PGC-1α, whereas overexpression of PGC-1α could rescue the changes. In addition, TMEM16A-induced fibrogenesis was dependent on increased intracellular Cl − , and reducing intracellular Cl − significantly blunted high glucose-induced PGC-1α and profibrotic factors expression. Taken together, our studies demonstrated that tubular TMEM16A promotes TIF by suppressing PGC-1α-mediated mitochondrial homeostasis in DKD. Blockade of TMEM16A may serve as a novel therapeutic approach to ameliorate TIF.
doi_str_mv 10.1007/s00018-023-05000-6
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In addition, TMEM16A-induced fibrogenesis was dependent on increased intracellular Cl − , and reducing intracellular Cl − significantly blunted high glucose-induced PGC-1α and profibrotic factors expression. Taken together, our studies demonstrated that tubular TMEM16A promotes TIF by suppressing PGC-1α-mediated mitochondrial homeostasis in DKD. 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Mol. Life Sci</addtitle><addtitle>Cell Mol Life Sci</addtitle><description>Tubulointerstitial fibrosis (TIF) plays a crucial role in the progression of diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain obscure. The present study aimed to examine whether transmembrane member 16A (TMEM16A), a Ca 2+ -activated chloride channel, contributes to the development of TIF in DKD. Interestingly, we found that TMEM16A expression was significantly up-regulated in tubule of murine model of DKD, which was associated with development of TIF. In vivo inhibition of TMEM16A channel activity with specific inhibitors Ani9 effectively protects against TIF. Then, we found that TMEM16A activation induces tubular mitochondrial dysfunction in in vivo and in vitro models, with the evidence of the TMEM16A inhibition with specific inhibitor. 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Mol. Life Sci</stitle><addtitle>Cell Mol Life Sci</addtitle><date>2023-12-01</date><risdate>2023</risdate><volume>80</volume><issue>12</issue><spage>347</spage><epage>347</epage><pages>347-347</pages><artnum>347</artnum><issn>1420-682X</issn><eissn>1420-9071</eissn><abstract>Tubulointerstitial fibrosis (TIF) plays a crucial role in the progression of diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain obscure. The present study aimed to examine whether transmembrane member 16A (TMEM16A), a Ca 2+ -activated chloride channel, contributes to the development of TIF in DKD. Interestingly, we found that TMEM16A expression was significantly up-regulated in tubule of murine model of DKD, which was associated with development of TIF. In vivo inhibition of TMEM16A channel activity with specific inhibitors Ani9 effectively protects against TIF. 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source Springer Nature; PubMed Central
subjects Animal models
Animals
Biochemistry
Biomedical and Life Sciences
Biomedicine
Calcium chloride
Calcium ions
Cell Biology
Channel gating
Chloride ions
Diabetes
Diabetes Mellitus
Diabetic Nephropathies - genetics
Diabetic nephropathy
Fibrosis
Homeostasis
Intracellular
Ion channels
Kidney diseases
Kidneys
Life Sciences
Mice
Mitochondria
Molecular modelling
Original
Original Article
therapeutics
title Tubular TMEM16A promotes tubulointerstitial fibrosis by suppressing PGC-1α-mediated mitochondrial homeostasis in diabetic kidney disease
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