The UBR5 protein facilitates mesangial cell hypertrophy and glycolysis induced by high glucose by increasing the phosphorylation levels of AKT_廖琳

 Lin Liao · Qiming Xu · Jie Xu · Jie Chen · Wenrui Liu · Wenhao Chen · Yunqing Tang · Lianxiang Duan · Yue Guo · Ziyang Liu · Pengyu Tao · Yu Cao · Jianrao Lu · Jing Hu1, 

 Abstract 

Aims One of the primary pathological features in the early stages of diabetic nephropathy is mesangial cell (MC) hypertrophy in the glomerulus. Considering the role of E3 ubiquitin ligases in regulating MC hypertrophy, the aim of this study was to identify the functional ubiquitin protein ligase E3 component N-recognin 5 (UBR5) during MC hypertrophy under high glucose conditions. 

Methods Human MCs (HMCs) transduced with UBR5 silencing or overexpression vector were treated with high glucose, AKT inhibitor, or glycolysis inhibitor. Cell proliferation, cell cycle, hypertrophy and glycolysis were evaluated in the HMCs after indicated treatment. m6A methylated RNA immunoprecipitation, luciferase reporter assay, and RNA immunoprecipitation were performed to determine the regulation of UBR5 by Wilms tumor 1-associating protein (WTAP)/insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) induced m6A modification. Western blot was performed to determine the protein expression levels. 

Results UBR5 expression was upregulated in db/db mice and in high glucose-induced HMCs. UBR5 silencing inhibited high glucose-induced HMC cell cycle arrest, cell hypertrophy, and glycolysis. UBR5 facilitated HMC hypertrophy and glycolysis by promoting the phosphorylation levels of AKT. Additionally, the promoting effect of glycolysis on cell hypertrophy were also elucidated. Further investigation into upstream regulators revealed that WTAP promoted m6A modification of UBR5 through the m6A reader IGF2BP1. 

Conclusions Our study unveils a novel mechanism involved in high glucose-induced cell hypertrophy, offering new insights into the understanding and treatment of early pathological mechanisms in diabetic nephropathy. 

Keywords High glucose · Hypertrophy · Glycolysis · UBR5, AKT phosphorylation 

目录