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

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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 Ca2+-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.

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The data that support the findings of this study are available on request from the corresponding author.

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Acknowledgements

This study was supported by the grants from the National Natural Science Foundation of China (82000648); the Natural Science Foundation of Jiangsu Province (BK20200363); the Outstanding Youth Cultivation Foundation of Southeast University (2021ZDYYYQPY07); the Fundamental Research Funds for the Central Universities (2242023K40046); the Innovative and Entrepreneurial Talent (Doctor) of Jiangsu Province; the Natural Science Foundation of Shandong Province (ZR2022MH161); the Science and Technology Planning Projects of Qingdao (2021-WJZD189 and 16-6-2-20-snh); and the Clinical Medicine + X Project of Affiliated Hospital of Qingdao University (3390).

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Author notes

  1. Jia-Ling Ji and Jun-Ying Li contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Jia-Ling Ji & Ai-Qing Zhang

  2. Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China

    Jun-Ying Li, Cong-Cong Liu, Yao Zhang & Rui-Xia Ma

  3. Department of Ultrasonography, Weifang People’s Hospital, Weifang, Shandong, China

    Jian-Xiang Liang

  4. Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China

    Yan Zhou, Hong Liu & Zuo-Lin Li

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  1. Jia-Ling Ji
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Contributions

JJL, and JYL designed the study, carried out the experiments, and analyzed the data; JXL, CCL, YZ, and AQZ analyzed the data, made the figures, and edited the paper; ZLL, RXM, and HL analyzed the data, made the figures, and wrote and edited the paper. All authors approved the final version of the paper.

Corresponding authors

Correspondence to Hong Liu, Rui-Xia Ma or Zuo-Lin Li.

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All animal experimental procedures were approved by the Ethics Review Committee for Animal Experimentation of Southeast University and were performed in accordance with the guidelines established by the National Institutes of Health for the Care and Use of Laboratory Animals.

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Ji, JL., Li, JY., Liang, JX. et al. Tubular TMEM16A promotes tubulointerstitial fibrosis by suppressing PGC-1α-mediated mitochondrial homeostasis in diabetic kidney disease. Cell. Mol. Life Sci. 80, 347 (2023). https://doi.org/10.1007/s00018-023-05000-6

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