HDAC9-mediated epithelial cell cycle arrest in G2/M contributes to kidney fibrosis in male mice

Yang Zhang, Yujie Yang, Fan Yang, Xiaohan Liu, Ping Zhan, Jichao Wu, Xiaojie Wang, Ziying Wang, Wei Tang, Yu Sun, Yan Zhang, Qianqian Xu, Jin Shang, Junhui Zhen, Min Liu () and Fan Yi ()
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Yang Zhang: Shandong University
Yujie Yang: Shandong University
Fan Yang: Provincial Hospital Affiliated to Shandong First Medical University
Xiaohan Liu: Shandong University
Ping Zhan: Shandong University
Jichao Wu: Shandong University
Xiaojie Wang: Shandong University
Ziying Wang: Shandong University
Wei Tang: Shandong University
Yu Sun: Shandong University
Yan Zhang: Shandong University
Qianqian Xu: Qilu Hospital of Shandong University
Jin Shang: the First Affiliated Hospital of Zhengzhou University
Junhui Zhen: Shandong University
Min Liu: Shandong University
Fan Yi: Shandong University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Renal tubular epithelial cells (TECs) play a key role in kidney fibrosis by mediating cycle arrest at G2/M. However, the key HDAC isoforms and the underlying mechanism that are involved in G2/M arrest of TECs remain unclear. Here, we find that Hdac9 expression is significantly induced in the mouse fibrotic kidneys, especially in proximal tubules, induced by aristolochic acid nephropathy (AAN) or unilateral ureter obstruction (UUO). Tubule-specific deletion of HDAC9 or pharmacological inhibition by TMP195 attenuates epithelial cell cycle arrest in G2/M, then reduces production of profibrotic cytokine and alleviates tubulointerstitial fibrosis in male mice. In vitro, knockdown or inhibition of HDAC9 alleviates the loss of epithelial phenotype in TECs and attenuates fibroblasts activation through inhibiting epithelial cell cycle arrest in G2/M. Mechanistically, HDAC9 deacetylates STAT1 and promotes its reactivation, followed by inducing G2/M arrest of TECs, finally leading to tubulointerstitial fibrosis. Collectively, our studies indicate that HDAC9 may be an attractive therapeutic target for kidney fibrosis.

Date: 2023
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DOI: 10.1038/s41467-023-38771-4

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