The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China.
Department of Neurosurgery, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
Nat Commun. 2023 May 25;14(1):3007. doi: 10.1038/s41467-023-38771-4.
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.
肾小管上皮细胞（TECs）通过介导 G2/M 期细胞周期停滞在肾脏纤维化中发挥关键作用。然而，参与 TECs G2/M 期阻滞的关键 HDAC 同工型和潜在机制仍不清楚。在这里，我们发现组蛋白去乙酰化酶 9（HDAC9）在由马兜铃酸肾病（AAN）或单侧输尿管梗阻（UUO）诱导的小鼠纤维化肾脏中，尤其是在近端小管中，表达显著上调。HDAC9 的小管特异性缺失或 TMP195 的药理学抑制可减轻 G2/M 期上皮细胞周期停滞，从而减少促纤维化细胞因子的产生，并减轻雄性小鼠的肾小管间质纤维化。在体外，HDAC9 的敲低或抑制通过抑制 G2/M 期上皮细胞周期停滞，减轻 TEC 中上皮表型的丧失，并减轻成纤维细胞的激活，从而减轻 TEC 中上皮表型的丧失，并减轻成纤维细胞的激活。在机制上，HDAC9 去乙酰化 STAT1 并促进其重新激活，随后诱导 TECs 的 G2/M 期阻滞，最终导致肾小管间质纤维化。总之，我们的研究表明，HDAC9 可能是肾脏纤维化的一个有吸引力的治疗靶点。
