Etoposide-induced protein 2.4 ameliorates high glucose-induced epithelial-mesenchymal transition by activating adenosine monophosphate-activated protein kinase pathway in renal tubular cells

Fan Li; Dongwei Guo; Shufeng Zhi; Keqi Jia; Yuxue Wang; Aobo Zhang; Yuqi Pei; Jun Hao

doi:10.1016/j.biocel.2021.106117

Etoposide-induced protein 2.4 ameliorates high glucose-induced epithelial-mesenchymal transition by activating adenosine monophosphate-activated protein kinase pathway in renal tubular cells

Int J Biochem Cell Biol. 2022 Jan:142:106117. doi: 10.1016/j.biocel.2021.106117. Epub 2021 Nov 19.

Authors

Fan Li¹, Dongwei Guo¹, Shufeng Zhi², Keqi Jia¹, Yuxue Wang², Aobo Zhang³, Yuqi Pei³, Jun Hao⁴

Affiliations

¹ Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei 050017,China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China.
² Department of Pediatrics, the Second Hospital of Hebei Medical University, Shijiazhuang, China.
³ College of Basic Medicine, Hebei Medical University, Shijiazhuang, China.
⁴ Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei 050017,China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China. Electronic address: haojun2004@hotmail.com.

PMID: 34801707
DOI: 10.1016/j.biocel.2021.106117

Abstract

Epithelial-mesenchymal transition (EMT), known as the transition of tubular epithelial cells into fibroblasts, is one of the potential mechanisms of renal fibrosis, which promotes the development of diabetic kidney disease (DKD). Etoposide-induced protein 2.4 (EI24) is known as an endoplasmic reticulum (ER)-localized Bcl-2-binding transmembrane protein with various functions that can affect autophagy, apoptosis and differentiation. However, whether EI24 is involved in EMT of renal tubular epithelial cells and the exact mechanism is still not known. In this study, we first reported that EI24 expression was significantly downregulated in the kidneys of diabetic mice and in high glucose-stimulated HK2 cells. Knockdown of EI24 led to EMT of HK2 cells, as indicated by decreased E-cadherin and increased α-smooth muscle actin (α-SMA). Meanwhile, overexpression of EI24 ameliorated high glucose-induced EMT of HK2 cells via activation of the adenosine monophosphate-activated protein kinase (AMPK) pathway. Then, DNA methyltransferase (DNMT) inhibitor 5-Aza-2'-deoxycytidine (5-Aza) treatment enhanced EI24 expression and alleviated EMT in high glucose-treated HK2 cells and the kidneys of diabetic mice. Furthermore, DNMT1 and DNMT3a upregulation were found to be involved in the decrease of EI24 in high glucose-stimulated HK2 cells. Silencing of DNMT1 and DNMT3a effectively reversed high glucose-induced downregulation of EI24 and aggravation of EMT. Our findings demonstrate that the DNA methyltransferase-regulated EI24 affects EMT of renal tubular cells via AMPK signaling pathway. It is suggested that EI24 may be a potential therapeutic target for diabetic renal injury.

Keywords: Adenosine monophosphate-activated protein kinase pathway; DNA methyltransferases; Diabetic kidney disease; Epithelial-mesenchymal transition; Etoposide-induced protein 2.4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Epithelial-Mesenchymal Transition*