EZH2 抑制或基因敲除可抑制常染色体显性多囊肾病中的囊肿生长。

EZH2 inhibition or genetic ablation suppresses cyst growth in autosomal dominant polycystic kidney disease.

机构信息

Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China.

Center for Clinical Laboratories, Affiliated Hospital of Guizhou Medical University, Guiyang City, Guizhou Province, China.

出版信息

J Transl Med. 2024 Oct 29;22(1):979. doi: 10.1186/s12967-024-05785-5.

DOI:10.1186/s12967-024-05785-5

PMID:39472935

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11520870/

Abstract

BACKGROUND

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent genetic disorder characterized by the formation of renal cysts leading to kidney failure. Despite known genetic underpinnings, the variability in disease progression suggests additional regulatory layers, including epigenetic modifications.

METHODS

We utilized various ADPKD models, including Pkd1 and Ezh2 conditional knockout (Pkd1:Ezh2) mice, to explore the role of Enhancer of Zeste Homolog 2 (EZH2) in cystogenesis. Pharmacological inhibition of EZH2 was performed using GSK126 or EPZ-6438 across multiple models.

RESULTS

EZH2 expression was significantly upregulated in Pkd1 cells, Pkd1 mice, and human ADPKD kidneys. EZH2 inhibition attenuates cyst development in MDCK cells and a mouse embryonic kidney cyst model. Both Ezh2 conditional knockout and GSK126 treatment suppressed renal cyst growth and protected renal function in Pkd1 mice. Mechanistically, cAMP/PKA/CREB pathway increased EZH2 expression. EZH2 mediated cystogenesis by enhancing methylation and activation of STAT3, promoting cell cycle through p21 suppression, and stimulating non-phosphorylated β-catenin in Wnt signaling pathway. Additionally, EZH2 enhanced ferroptosis by inhibiting SLC7A11 and GPX4 in ADPKD.

CONCLUSION

Our findings elucidate the pivotal role of EZH2 in promoting renal cyst growth through epigenetic mechanisms and suggest that EZH2 inhibition or ablation may serve as a novel therapeutic approach for managing ADPKD.

摘要

背景

常染色体显性多囊肾病（ADPKD）是一种常见的遗传性疾病，其特征是形成导致肾衰竭的肾囊肿。尽管已知存在遗传基础，但疾病进展的可变性表明存在其他调节层，包括表观遗传修饰。

方法

我们利用了各种 ADPKD 模型，包括 Pkd1 和 Ezh2 条件性敲除（Pkd1:Ezh2）小鼠，来探索 Enhancer of Zeste Homolog 2（EZH2）在囊肿形成中的作用。使用 GSK126 或 EPZ-6438 在多种模型中对 EZH2 进行了药理学抑制。

结果

EZH2 在 Pkd1 细胞、Pkd1 小鼠和人类 ADPKD 肾脏中表达显著上调。EZH2 抑制可减轻 MDCK 细胞和小鼠胚胎肾囊肿模型中的囊肿发育。Ezh2 条件性敲除和 GSK126 治疗均可抑制 Pkd1 小鼠的肾囊肿生长并保护肾功能。机制上，cAMP/PKA/CREB 通路增加了 EZH2 的表达。EZH2 通过增强 STAT3 的甲基化和激活、通过抑制 p21 来促进细胞周期、通过刺激 Wnt 信号通路中的非磷酸化β-catenin，促进囊肿发生。此外，EZH2 通过抑制 SLC7A11 和 GPX4 增强 ADPKD 中的铁死亡。