ER Stress-Perturbed Intracellular Protein O-GlcNAcylation Aggravates Podocyte Injury in Diabetes Nephropathy

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Dec 23

PMID 38139429

Authors

Shicong Song

Tiantian Hu

Xu Shi

Yongjie Jin

Sirui Liu

Xuehong Li

Wei Zou

Cheng Wang

Affiliations

Soon will be listed here.

Abstract

Diabetes nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide, and podocyte injury is the central contributor to the progression of DN. Despite the emerging evidence that has established the importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of DN, abnormal protein O-GlcNAcylation is also augmented. Currently, the mechanism associating these two hyperglycemia-induced disorders remains poorly understood. This study intended to elucidate whether ER stress drives hyper-protein O-GlcNAcylation to cause podocyte injury in DN. We used both type 1 and type 2 DN models to confirm the occurrence of ER stress and excessive protein O-GlcNAcylation, and then podocyte purification was also conducted for further investigation. Nephroseq V5 data were mined and in vitro studies were applied to reveal the involvement of ER stress and hyper-O-GlcNAcylation in podocyte injury. Our results indicated that ER stress was induced in both type 1 and type 2 DN, and the human RNA-seq data from Nephroseq V5 showed that O-GlcNAcylation-related genes were significantly upregulated in the DN patients. We further demonstrated that ER stress occurred prior to hyper-O-GlcNAc modification and that pharmacologically inhibited protein O-GlcNAcylation can help decrease the podocyte apoptosis induced by hyperglycemia. Together, these discoveries will aid in uncovering the activation of the ER stress-O-GlcNAcylation axis in podocyte injury under DN, which will help open up new therapeutic approaches for preventing DN progression.

Citing Articles

Efficacy and potential pharmacological mechanism of combination in diabetic nephropathy: integrating meta-analysis, network pharmacology, molecular docking, and experimental validation.

Liang H, Chen Z, Zhu M, Zhong J, Lin S, Chen J Ren Fail. 2025; 47(1):2466116.

PMID: 40015687 PMC: 11869347. DOI: 10.1080/0886022X.2025.2466116.

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