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

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 ubiquitylating G6PD on K366 and K403. In summary, our data suggest that high glucose induces ubiquitination of G6PD by VHL E3 ubiquitin ligase, which leads to ROS accumulation and podocyte injury.—Wang, M., Hu, J., Yan, L., Yang, Y., He, M., Wu, M., Li, Q., Gong, W., Yang, Y., Wang, Y., Handy, D. E., Lu, B., Hao, C., Wang, Q., Li, Y., Hu, R., Stanton, R. C., Zhang, Z. High glucose—induced ubiquitination of G6PD leads to the injury of podocytes. FASEB J. 33, 6296–6310 (2019). http://www.fasebj.org

Caffeine Targets G6PDH to Disrupt Redox Homeostasis and Inhibit Renal Cell Carcinoma Proliferation

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Glucose‐6‐phosphate dehydrogenase is posttranslationally regulated in the larvae of the freeze‐tolerant gall fly, Eurosta solidaginis, in response to freezing

“…Given the unchanged G6PDH activity levels in the crude insect homogenates and the constant V max calculated from the purified enzyme samples, it seems likely that the reduction in ubiquitin levels may be necessary to maintain levels of G6PDH during the winter months to help the animal cope with repeat freeze‐thaw cycles. Interestingly, ubiquitin is known to mediate G6PDH expression levels in the human kidney where elevated levels of glucose result in an increase in G6PDH ubiquitination resulting in a depletion of this enzyme and subsequent oxidative stress due to decreased NADPH pools (Wang et al, ). The results here raise additional questions regarding whether this decrease in ubiquitin levels is unique to this enzyme or if a reduction in ubiquitin ligation is a feature common to many proteins in E. solidaginis as an over‐wintering response.…”

The role of ubiquitination and deubiquitination in cancer metabolism

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