O-GlcNAcylation regulates HIF-1α and induces mesothelial-mesenchymal transition and fibrosis of human peritoneal mesothelial cells

Jian Wang; Xin Lv; Ashanjiang Aniwan; Hongyan Liu; Yao Lin; Xian Shao; Saijun Zhou; Pei Yu

doi:10.1016/j.heliyon.2023.e22916

O-GlcNAcylation regulates HIF-1α and induces mesothelial-mesenchymal transition and fibrosis of human peritoneal mesothelial cells

Heliyon. 2023 Dec 1;9(12):e22916. doi: 10.1016/j.heliyon.2023.e22916. eCollection 2023 Dec.

Authors

Jian Wang^{1

2}, Xin Lv^{2

3}, Ashanjiang Aniwan², Hongyan Liu², Yao Lin², Xian Shao², Saijun Zhou², Pei Yu²

Affiliations

¹ Department of Nephrology, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
² NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
³ Department of Nephrology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.

Abstract

O-GlcNAcylation is a post-translational modification of proteins that regulates various biological processes. However, its involvement in peritoneal dialysis fibrosis remains unclear. This study aimed to investigate the impact of O-GlcNAcylation on human peritoneal mesothelial cells (HPMCs) cultured in control and high-glucose medium. To manipulate cellular conditions, we employed knockdown techniques targeting HIF-1α and OGT, along with the administration of pharmacological agents (PUGNAc, OSMI-1, MG-132, FG-4592, and HIF-1α inhibitor). Our findings revealed that elevated glucose levels increased global O-GlcNAcylation and the abundance of HIF-1α, α-SMA, fibronectin, and COL1A2. Conversely, the expression of E-Cadherin was decreased. Significantly, a positive correlation was observed between O-GlcNAcylation, HIF-1α, mesothelial-to-mesenchymal transition (MMT), and fibrosis in HPMCs. Notably, O-GlcNAcylation was found to regulate HIF-1α, thereby promoting MMT and fibrosis under high glucose conditions. Furthermore, we discovered that high glucose levels induced O-GlcNAcylation of HIF-1α, preventing its ubiquitination and proteasomal degradation. In summary, our study demonstrates the critical role of O-GlcNAcylation-mediated regulation of HIF-1α in MMT and fibrosis during peritoneal dialysis.

Keywords: Fibrosis; HIF-1α; MMT; O-GlcNAcylation; Peritoneal dialysis.