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

Autor: Lv J; Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China., Lan B; Center for Clinical Laboratories, Affiliated Hospital of Guizhou Medical University, Guiyang City, Guizhou Province, China.; Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China., Fu L; Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China., He C; Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China., Zhou W; Department of Nephrology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China., Wang X; Institute of Infectious Diseases, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.; Beijing Institute of Infectious Diseases, Beijing, 100015, China., Zhou C; Outpatient Department, Yangpu Third Military Retreat, Shanghai, China., Mao Z; Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China. maozhiguo93@163.com., Chen Y; Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China. ychen@tmu.edu.cn., Mei C; Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China. changlinmei@smmu.edu.cn., Xue C; Kidney Institute, Division of Nephrology, Shanghai Changzheng Hospital, Second Military Medical University (Naval Medical University), 415 Fengyang Road, Shanghai, 200003, China. chengxia1568@126.com.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2024 Oct 29; Vol. 22 (1), pp. 979. Date of Electronic Publication: 2024 Oct 29.
DOI: 10.1186/s12967-024-05785-5
Abstrakt: 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 delta/delta :Ezh2 delta/delta ) 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 delta/delta 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 delta/delta 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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