Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1

Kai Ai; Xiaozhou Li; Pan Zhang; Jian Pan; Huiling Li; Zhibiao He; Hongliang Zhang; Lei Yi; Ye Kang; Yinhuai Wang; Junxiang Chen; Yijian Li; Xudong Xiang; Xiangping Chai; Dongshan Zhang

doi:10.1016/j.omtn.2022.02.015

Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1

Mol Ther Nucleic Acids. 2022 Feb 28:28:77-86. doi: 10.1016/j.omtn.2022.02.015. eCollection 2022 Jun 14.

Authors

Kai Ai^{1

2

3}, Xiaozhou Li^{1

2}, Pan Zhang^{1

2

4}, Jian Pan^{1

2}, Huiling Li⁵, Zhibiao He^{1

2}, Hongliang Zhang^{1

2}, Lei Yi³, Ye Kang³, Yinhuai Wang³, Junxiang Chen⁶, Yijian Li³, Xudong Xiang^{1

2}, Xiangping Chai^{1

2}, Dongshan Zhang^{1

2}

Affiliations

¹ Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.
² Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.
³ Department of Urology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.
⁴ Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan 410011, People's Republic of China.
⁵ Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.
⁶ Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.

Abstract

DNA methylation plays a pivotal role in the progression of renal fibrosis. Methyl-CpG-binding domain protein 2 (MBD2), a protein reader of methylation, is involved in the development of acute kidney injury (AKI) caused by vancomycin. However, the role and mechanism of action of MBD2 in renal remain unclear. In this study, MBD2 mediated extracellular matrix (ECM) production induced by TGF-β1 in Boston University mouse proximal tubule (BUMPT) cells，and upregulated the expression EGR1 to promote ECM production in murine embryonic NIH 3T3 fibroblasts. ChIP analysis demonstrated that MBD2 physically interacted with the promoter region of the CpG islands of EGR1 genes and then activated their expression by inducing hypomethylation of the promoter region. In vivo, PT-MBD2-KO attenuated unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis via downregulation of EGR1, which was demonstrated by the downregulation of fibronectin (FN), collagen I and IV, α-SMA, and EGR1. Injection of MBD2-siRNA attenuated the UUO- and I/R-induced renal fibrosis. Those molecular changes were verified by biopsies from patients with obstructive nephropathy (OB). These data collectively demonstrated that inhibition of MBD2 reduces renal fibrosis via downregulating EGR1, which could be a target for treatment of fibrotic kidney disease.

Keywords: EGR1; I/R; MBD2; MT: Bioinformatics; UUO; renal fibrosis.