OGT-mediated O-GlcNAc of PINK1 promotes the progression of obesity-related hypertension via regulating mitophagy.

Abstract

Background: Obesity causes a variety of metabolic diseases, including hypertension. O-linked beta-N-acetylglucosamine (O-GlcNAc), a dynamic post-translational modification, is rapidly cycled on and off proteins by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Our study hypothesized that O-GlcNAc contributes to the progression of obesity-related hypertension (OH). Using in vivo and in vitro approaches, we systematically investigated the role of O-GlcNAc in OH pathogenesis and elucidated its molecular mechanisms.

Methods: An in vivo OH rat model was established through feeding with a high-fat diet. Besides, A7r5 cells were treated with oxidized low-density lipoprotein (ox-LDL) to simulate OH in vitro. Western blot was used to detect the protein levels of O-GlcNAc, OGT, OGA, and autophagy-related indicators. CCK-8 was performed to analyze the cell viability. The apoptosis rate was assessed by flow cytometry. Co-immunoprecipitation was performed to verify the endogenous interaction between OGT and PTEN-induced putative kinase (PINK)1.

Results: OGT-mediated O-GlcNAc was elevated in both in vivo and in vitro OH models. Besides, OGT deficiency inhibited hypertension and inflammation, and increased autophagy in high-fat diet-induced OH rats. Additionally, OGT inhibition increased cell viability and autophagy and inhibited apoptosis in ox-LDL-treated A7r5 cells. Mechanically, OGT-mediated O-GlcNAc of PINK1 at S335 site regulated the phosphorylation of PINK1. Finally, PINK1 inhibition decreased cell viability and autophagy and promoted apoptosis in ox-LDL-treated A7r5 cells.

Conclusion: OGT-mediated O-GlcNAc of PINK1 promoted the progression of OH via regulating mitophagy, which might provide a new insight for OH treatment.