High glucose-induced ubiquitination of G6PD leads to the injury of podocytes

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Meng WangZhaoyun Zhang

Abstract

Oxidative stress contributes substantially to podocyte injury, which plays an important role in the development of diabetic kidney disease. The mechanism of hyperglycemia-induced oxidative stress in podocytes is not fully understood. Glucose-6-phosphate dehydrogenase (G6PD) is critical in maintaining NADPH, which is an important cofactor for the antioxidant system. Here, we hypothesized that high glucose induced ubiquitination and degradation of G6PD, which injured podocytes by reactive oxygen species (ROS) accumulation. We found that G6PD protein expression was decreased in kidneys of both diabetic patients and diabetic rodents. G6PD activity was also reduced in diabetic mice. Overexpressing G6PD reversed redox imbalance and podocyte apoptosis induced by high glucose and palmitate. Inhibition of G6PD with small interfering RNA induced podocyte apoptosis. In kidneys of G6PD-deficient mice, podocyte apoptosis was significantly increased. Interestingly, high glucose had no effect on G6PD mRNA expression. Decreased G6PD protein expression was mediated by the ubiquitin proteasome pathway. We found that the von Hippel-Lindau (VHL) protein, an E3 ubiquitin ligase subunit, directly bound to G6PD and degraded G6PD through ubiquitylatin...Continue Reading

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Citations

Sep 11, 2019·Cells·Hung-Chi YangDaniel Tsun-Yee Chiu
Oct 3, 2020·Molecular Cancer·Tianshui SunQing Yang
Jun 26, 2020·Frontiers in Endocrinology·Tongxin GeXuemei Tong
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Dec 19, 2021·Frontiers of Medicine·Jiabing ZhanHuaping Li

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