HDAC9-mediated epithelial cell cycle arrest in G2/M contributes to kidney fibrosis in male mice
Related Experiment Video
Updated: Jul 29, 2025
Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis
Published on: April 25, 2025
Yang Zhang1, Yujie Yang1, Fan Yang2
1The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China.
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.
Insights
Histone deacetylase 9 (HDAC9) drives kidney fibrosis by causing renal tubular epithelial cells to arrest. Inhibiting HDAC9 reduces fibrosis, suggesting it as a potential therapeutic target.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Renal tubular epithelial cells (TECs) are crucial in kidney fibrosis, mediating cell cycle arrest at G2/M.
- The specific histone deacetylase (HDAC) isoforms and mechanisms driving TEC G2/M arrest in fibrosis are not fully understood.
Purpose of the Study:
- To identify the key HDAC isoforms involved in TEC G2/M arrest during kidney fibrosis.
- To elucidate the underlying molecular mechanisms linking HDACs to fibrosis progression.
- To evaluate HDAC9 as a potential therapeutic target for kidney fibrosis.
Main Methods:
- Investigated Hdac9 expression in mouse models of kidney fibrosis (aristolochic acid nephropathy and unilateral ureter obstruction).
- Utilized tubule-specific Hdac9 deletion and pharmacological inhibition (TMP195) in vivo.
- Performed in vitro experiments involving TECs with Hdac9 knockdown or inhibition.
- Analyzed epithelial cell cycle arrest, profibrotic cytokine production, fibroblast activation, and STAT1 acetylation/reactivation.
Main Results:
- Hdac9 expression was significantly upregulated in fibrotic mouse kidneys, particularly in proximal tubules.
- Tubule-specific deletion or pharmacological inhibition of HDAC9 attenuated G2/M arrest in TECs, reduced profibrotic factors, and alleviated tubulointerstitial fibrosis.
- In vitro, HDAC9 inhibition protected TECs from losing their epithelial phenotype and reduced fibroblast activation by preventing G2/M arrest.
- Mechanistically, HDAC9 was found to deacetylate and reactivate STAT1, leading to TEC G2/M arrest and subsequent fibrosis.
Conclusions:
- HDAC9 plays a critical role in mediating G2/M cell cycle arrest in TECs during kidney fibrosis.
- HDAC9-STAT1 signaling is a key pathway driving tubulointerstitial fibrosis.
- HDAC9 represents a promising therapeutic target for mitigating kidney fibrosis.
