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

by Selleckchem | Aug 07 2023

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.

Comments:

The passage describes a study that investigated the role of renal tubular epithelial cells (TECs) in kidney fibrosis and identified HDAC9 as a key player in mediating cell cycle arrest at G2/M, leading to tubulointerstitial fibrosis. The study utilized mouse models of kidney fibrosis induced by aristolochic acid nephropathy (AAN) or unilateral ureter obstruction (UUO) and examined the effects of HDAC9 inhibition on TECs.

The researchers found that Hdac9 expression was significantly increased in fibrotic kidneys, particularly in the proximal tubules. By specifically deleting HDAC9 in the tubules or using a pharmacological inhibitor called TMP195, they observed a reduction in TECs' cycle arrest at G2/M. This attenuation of cell cycle arrest resulted in decreased production of profibrotic cytokines and alleviation of tubulointerstitial fibrosis in male mice.

In vitro experiments using TECs further supported these findings. Knockdown or inhibition of HDAC9 prevented the loss of the epithelial phenotype in TECs and attenuated the activation of fibroblasts by inhibiting cell cycle arrest at G2/M.

Mechanistically, HDAC9 was found to deacetylate STAT1 and promote its reactivation. This reactivated STAT1, in turn, induced G2/M arrest in TECs, ultimately leading to tubulointerstitial fibrosis.

Based on these results, the researchers suggest that HDAC9 could serve as a potential therapeutic target for kidney fibrosis. By inhibiting HDAC9, it may be possible to alleviate TECs' cell cycle arrest, reduce profibrotic cytokine production, and mitigate tubulointerstitial fibrosis. However, further research is necessary to validate these findings and explore the translational potential of targeting HDAC9 in treating kidney fibrosis.