High glucose-induced ubiquitination of G6PD leads to the injury of podocytes
High glucose-induced ubiquitination of G6PD leads to the injury of podocytes
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DOI：
10.1096/fj.201801921r
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发表时间：
2019-05-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Zhaoyun
中科院分区：
文献类型：
--
作者：
Wang, Meng;Hu, Ji;Zhang, Zhaoyun
氧化应激是足细胞损伤的主要原因，足细胞损伤在糖尿病肾病的发生发展中起重要作用。高血糖诱导足细胞氧化应激的机制尚未完全清楚。葡萄糖-6-磷酸脱氢酶（G6 PD）是维持NADPH的关键，NADPH是抗氧化系统的重要辅助因子。在这里，我们假设，高糖诱导泛素化和降解的G6 PD，损伤足细胞的活性氧（ROS）的积累。我们发现G6 PD蛋白在糖尿病患者和糖尿病啮齿类动物的肾脏中表达减少。G6 PD活性在糖尿病小鼠中也降低。过表达G6 PD逆转高糖和棕榈酸诱导的氧化还原失衡和足细胞凋亡。用小干扰RNA抑制G6 PD诱导足细胞凋亡。在G6 PD缺陷小鼠的肾脏中，足细胞凋亡显著增加。有趣的是，高糖对G6 PD mRNA表达没有影响。G6 PD蛋白表达的降低是由泛素蛋白酶体途径介导的。我们发现，von Hippel-Lindau（VHL）蛋白，一种E3泛素连接酶亚基，直接与G6 PD结合，并通过泛素化K-366和K-403上的G6 PD来降解G6 PD。总之，我们的数据表明高葡萄糖通过VHL E3泛素连接酶诱导G6 PD的泛素化，这导致ROS积累和足细胞损伤。胡，J，延湖，加-地杨，Y.，他，M.，吴，M.，李，Q.，龚，W.，杨，Y.，王玉，Handy，D. E、Lu，B.，郝，C.，王建奎，李，Y.，胡河，斯坦顿河C.的方法，Zhang，Z.高糖诱导的G6 PD泛素化导致足细胞损伤。
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 K-366 and K-403. 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.