TWIK-related acid-sensitive K+ channel 2 promotes renal fibrosis by inducing cell-cycle arrest

Jian Zhang; Jing Chen; Yufei Lu; Yan Yang; Weize Chen; Bo Shen; Jiachang Hu; Ping Jia; Sujuan Xu; Yiqin Shi; Yichun Ning; Jialin Wang; Yi Fang; Shuan Zhao; Yang Li; Yan Dai; Xiaoyan Zhang; Meng Xiang; Yang Tian; Zhichao Liu; Nana Song; Xiaoqiang Ding

doi:10.1016/j.isci.2022.105620

TWIK-related acid-sensitive K⁺ channel 2 promotes renal fibrosis by inducing cell-cycle arrest

iScience. 2022 Nov 17;25(12):105620. doi: 10.1016/j.isci.2022.105620. eCollection 2022 Dec 22.

Authors

Jian Zhang^{1

2}, Jing Chen^{2

3

4

5

6}, Yufei Lu^{2

3

4

5

6}, Yan Yang^{2

3

4

5

6}, Weize Chen^{2

3

4

5

6}, Bo Shen^{2

3

4

5

6}, Jiachang Hu^{2

3

4

5

6}, Ping Jia^{2

3

4

5

6}, Sujuan Xu^{2

3

4

5

6}, Yiqin Shi^{2

3

4

5

6}, Yichun Ning^{2

3

4

5

6}, Jialin Wang^{2

3

4

5

6}, Yi Fang^{2

3

4

5

6}, Shuan Zhao^{2

3

4

5

6}, Yang Li^{2

3

4

5

6}, Yan Dai^{2

3

4

5

6}, Xiaoyan Zhang^{2

3

4

5

6}, Meng Xiang⁷, Yang Tian⁸, Zhichao Liu⁸, Nana Song^{2

3

4

5

6

9}, Xiaoqiang Ding^{2

3

4

5

6}

Affiliations

¹ Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
² Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
³ Shanghai Medical Center of Kidney, Shanghai 200032, China.
⁴ Shanghai Institute of Kidney and Dialysis, Shanghai 200032, China.
⁵ Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai 200032, China.
⁶ Hemodialysis Quality Control Center of Shanghai, Shanghai 200032, China.
⁷ Department of Physiology and Pathophysiology, Fudan University, Shanghai 200032, China.
⁸ Department of Chemistry, East China Normal University, Shanghai 200241, China.
⁹ Fudan Zhangjiang Institute, Shanghai 201203, China.

Abstract

TWIK-related acid-sensitive K⁺ channel-2 (TASK-2, encoded by Kcnk5) is essential in cell biological processes, by regulating transmembrane K⁺ balance. In the present study, we aimed to clarify the role of TASK-2 in renal fibrosis and explore the underlying mechanism. We found that TASK-2 level was elevated in the renal tubular UUO- and UIR-induced renal fibrosis as well as in patients with renal tubulointerstitial fibrosis. Knockout of Kcnk5 or inhibition of TASK-2 in renal tubules attenuated G2/M cell-cycle arrest and alleviated renal fibrosis. Mechanistically, demethylase fat mass and obesity-associated protein (FTO) reduced N6-adenosine methylation (m6A) of Kcnk5 mRNA following renal fibrosis. FTO deficiency attenuated the upregulation of TASK-2 and renal fibrosis. The results demonstrated the crucial role of TASK-2 in renal fibrosis, which is conducive to a better understanding of the pathogenesis of renal fibrosis. TASK-2 may be a potential treatment strategy to alleviate the development of renal fibrosis.

Keywords: Nephrology; cell biology; molecular biology.

Associated data

Dryad/10.5061/dryad.r2280gbbz