Proximal tubular EZH2 inhibits diabetic kidney disease by suppressing SHC1-mediated oxidative stress-Qiming Xu

 Qiming Xu^a,b,c,d,1, Pinglan Lin^a,b,c,1, Sijun Chen^e,1, Jianrao Lu^d, Lin Li^f, Reza Moghadasali^g, Xuejun Yang^a,b,c, Jing Hu^d,***, Ming Wu^a,b,c,**, Dongping Chen^a,b,c,*

^aDepartment of Nephrology, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, PR China^bTCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine, PR China^cKey Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, PR China^dDepartment of Nephrology, Shanghai Seventh People’s Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, PR China^eDepartment of Nephrology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, PR China^fDepartment of Nephrology, Shanghai Changzheng Hospital (Second Affiliated Hospital of Naval Medical University), Shanghai, PR China^gDepartment of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

ARTICLE INFO

Keywords:

EZH2Diabetic kidney diseaseRenal tubuleSHC1Oxidative stress

ABSTRACT

Diabetic kidney disease (DKD) represents one of the most severe complications of diabetes. Although EZH2 (Enhancer of Zeste Homolog 2) has been implicated in renal injury and diabetes, its specific function within renal tubular cells in DKD remains unclear. Here, we explored the role and downstream mechanism of tubular EZH2 in DKD progression.

Renal EZH2 expression was significantly upregulated in DKD. Single-nucleus RNA sequencing and immuno-fluorescence analyses verified that such elevation was restricted to proximal tubular epithelial cells. Conversely, tubular-specific deletion of Ezh2 exacerbated renal dysfunction and fibrosis in DKD mice. In vitro gain- and loss- of-function experiments in high glucose-stimulated HK2 cells further validated that EZH2 plays a renoprotective role under diabetic conditions. Mechanistically, we demonstrated that EZH2 epigenetically suppresses the pro- oxidative mediator SHC1. In the DKD mouse model, renal SHC1 protein abundance was markedly increased upon tubular Ezh2 knockout, accompanied by reduced levels of antioxidant enzymes SOD1 and SOD2, signifi-cantly elevated MDA, and depleted GSH. Consistent with these in vivo observations, in vitro functional assays further validated that EZH2 epigenetically downregulates SHC1 and alleviates such oxidative stress perturba-tions. Finally, we verified that SHC1 inhibition rescues the exacerbated fibrotic response and oxidative damage triggered by pharmacological EZH2 suppression under high-glucose conditions.

In conclusion, tubular EZH2 protects against DKD via inhibiting SHC1-driven oxidative stress.

1.Introduction[3]. Renal tubules play a crucial role in maintaining kidney function [4]. In DKD, tubular injury emerges as an early and prominent pathological 

Diabetic kidney disease (DKD), a major complication of diabetes, is feature, often preceding glomerular damage [4]. Tubular epithelial cells the leading cause of end-stage renal disease (ESRD) in developed nations are highly vulnerable to diabetes-related metabolic stresses, such as [1,2]. Beyond significantly compromising patients’ quality of life, DKD hyperglycemia, hyperlipidemia, and oxidative stress [5]. Such injury imposes a substantial economic burden on healthcare systems globally disrupts normal tubular reabsorption and secretion, activates 

*Corresponding author. Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Pudong District, Shanghai, 201203, PR China.**Corresponding author. Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Pudong District, Shanghai, 201203, PR China.***Corresponding author.

E-mail addresses: hu12340714@163.com(J. Hu), mingwunl@126.com(M. Wu), 13764362569@163.com(D. Chen). ¹These authors contributed equally to this paper.

Received 7 January 2026; Received in revised form 21 July 2026; Accepted 8 August 2026 

Availableonline10August20260891-5849/©2026PublishedbyElsevierInc.