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, Fan Yi

Nature communications 2023 May 25

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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. © 2023. The Author(s).

Citation

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, Fan Yi. HDAC9-mediated epithelial cell cycle arrest in G2/M contributes to kidney fibrosis in male mice. Nature communications. 2023 May 25;14(1):3007