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Inhibition of TMEM16A improves cisplatin-induced acute kidney injury via preventing DRP1-mediated mitochondrial fission

Acta Pharmacologica Sinica volumeĀ 44,Ā pages 2230ā€“2242 (2023)Cite this article

Abstract

Acute kidney injury (AKI) is associated with high morbidity and mortality. Our previous study has demonstrated that TMEM16A, a Ca2+-activated chloride channel, contributes to renal fibrosis progression in chronic kidney disease. However, whether TMEM16A isĀ involved in AKI is still unknown. In this study, we established cisplatin AKI mice model and found that TMEM16A expression was upregulated in the injured kidney. In vivo knockdown of TMEM16A effectively prevented cisplatin-induced tubular cell apoptosis, inflammation and kidney function loss. Western blot and transmission electron microscopy (TEM) revealed that TMEM16A knockdown inhibited Drp1 translocation from the cytoplasm to mitochondria and prevented mitochondrial fission in tubular cells. Consistently, in cultured HK2 cells, knockdown or inhibition of TMEM16A by shRNA or its specific inhibitor suppressed cisplatin-induced mitochondrial fission and its associated energy dysfunction, ROS accumulation, and cell apoptosis via inhibiting Drp1 activation. Further investigation showed that genetic knockdown or pharmacological inhibition of TMEM16A inhibited cisplatin-induced Drp1 Ser-616 site phosphorylation through ERK1/2 signaling pathway, whereas overexpression of TMEM16A promoted this effect. Treatment with Drp1 or ERK1/2 inhibitor could efficiently prevent cisplatin-induced mitochondrial fission. Collectively, our data suggest that TMEM16A inhibition alleviated cisplatin-induced AKI by preventing tubular cell mitochondrial fission through the ERK1/2 / Drp1 pathway. Inhibition of TMEM16A may be a novel therapeutic strategy for AKI.

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Fig. 1: Knockdown of TMEM16A improved cisplatin-induced AKI.
Fig. 2: Knockdown of TMEM16A alleviated cisplatin-induced kidney injury and cell apoptosis in mouse kidneys.
Fig. 3: Knockdown or inhibition of TMEM16A prevented cisplatin-induced HK2 cell apoptosis.
Fig. 4: Knockdown or inhibition of TMEM16A prevented cisplatin-induced mitochondrial fission in vivo and in vitro.
Fig. 5: Knockdown of TMEM16A prevented cytochrome c release, mitochondrial dysfunction, and mitochondrial ROS accumulation.
Fig. 6: Knockdown or inhibition of TMEM16A prevented the translocation of Drp1 to mitochondria.
Fig. 7: TMEM16A promoted Drp1 phosphorylation via ERK1/2 signaling.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 82173809, 81872858, 82200750), the Science and Technology Planning Project of Guangzhou, China (No. 202102080012), the Natural Science Foundation of Guangdong Province, China (No. 2022A1515012197, 2023A1515010468), and the Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515110222).

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  1. These authors contributed equally: Xiao-long Li, Xue-wu Liu

Authors and Affiliations

  1. Department of Pharmacology, Cardiac & Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China

    Xiao-long Li,Ā Xue-wu Liu,Ā Wei-ling Liu,Ā Yu-quan Lin,Ā Yu-sheng Peng,Ā Li-min ChengĀ &Ā Yan-hua Du

  2. State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Xiao-long Li

  3. Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China

    Jing Liu

  4. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Li-min Cheng

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Contributions

XLL performed the animal experiments, and Western blots. XWL performed the immunofluorescence staining, cell culture and transfection. WLL and LMC carried out the tissue slides preparation. YQL, YSP and JL carried out the animal feeding. XLL and YHD conceived the study and drafted the manuscript.

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Correspondence to Li-min Cheng or Yan-hua Du.

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Li, Xl., Liu, Xw., Liu, Wl. et al. Inhibition of TMEM16A improves cisplatin-induced acute kidney injury via preventing DRP1-mediated mitochondrial fission. Acta Pharmacol Sin 44, 2230ā€“2242 (2023). https://doi.org/10.1038/s41401-023-01122-6

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