HRD1-Mediated IGF-1R Ubiquitination Contributes to Renal Protection of Resveratrol in db/db Mice
HRD1-Mediated IGF-1R Ubiquitination Contributes to Renal Protection of Resveratrol in db/db Mice
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HRD1 介导的 IGF-1R 泛素化有助于白藜芦醇对 db/db 小鼠的肾脏保护
DOI：
10.1210/me.2015-1277
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发表时间：
2016-06-01
影响因子：
--
通讯作者：
Liang, Xiubin
中科院分区：
文献类型：
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作者：
Yan, Caifeng;Xu, Weifeng;Liang, Xiubin
许多研究提供了证据证明白藜芦醇（RESV）的有益肾脏作用，这是由于其抗氧化特性和激活苏球蛋白1的能力。然而，RESV对肾损伤保护作用的分子机制仍不完全清楚。本研究以Lepr db/db（db/db）和Lepr db/m（db/m）小鼠为模型，观察RESV对糖尿病肾病（DN）的影响。RESV可减少db/db小鼠的蛋白尿并减轻肾纤维化的进展。RESV治疗显著减弱了糖尿病诱导的db/db小鼠肾脏超氧化物歧化酶铜/锌、超氧化物歧化酶锰、过氧化氢酶和丙二醛的变化，以及肾脏烟酰胺腺嘌呤二核苷酸磷酸氧化酶4（NOX 4）、α-平滑肌肌动蛋白（α-SMA）和E-钙粘蛋白的表达。db/db小鼠肾脏中IGF-1受体（IGF-1 R）的表达增加，但DN模型中3-羟基-3-甲基戊二酸还原酶降解（HRD 1）（一种遍在蛋白E3连接酶）的表达显着降低。RESV处理显著降低IGF-1 R和增加HRD 1表达，与用HKC-8细胞获得的数据一致。HRD 1在HKC-8细胞中与IGF-1 R发生物理相互作用，液相色谱和串联质谱（LC-MS/MS）数据支持IGF-1 R是HRD 1底物之一的概念。HRD 1可促进IGF-1 R泛素化降解，HRD 1的下调可逆转RESV对HKC-8细胞的保护作用。总之，我们已经证明，RESV减少蛋白尿，并减弱db/db小鼠肾纤维化的进展。RESV对DN的保护作用可能与其上调HRD 1的表达，促进IGF-1 R的泛素化和降解有关。
Many studies have provided evidence to demonstrate the beneficial renal effects of resveratrol (RESV) due to its antioxidant character and its capacity for activation of surtuin 1. However, the molecular mechanisms underlying the protective role of RESV against kidney injury are still incompletely understood. The present study used Lepr db/db (db/db) and Lepr db/m (db/m) mice as models to evaluate the effect of RESV on diabetic nephropathy (DN). RESV reduced proteinuria and attenuated the progress of renal fibrosis in db/db mice. Treatment with RESV markedly attenuated the diabetes-induced changes in renal superoxide dismutase copper/zinc, superoxide dismutase manganese, catalase, and malonydialdehyde as well as the renal expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), alpha-smooth muscle actin (alpha-SMA), and E-cadherin in db/db mice. The kidney expression of the IGF-1 receptor (IGF-1R) was increased in db/db mice, but the expression of 3-hydroxy-3-methylglutaryl reductase degradation (HRD1), a ubiquitin E3 ligase, was significantly decreased in the DN model. RESV treatment dramatically decreased IGF-1R and increased HRD1 expressions, consistent with data obtained with HKC-8 cells. HRD1 physically interacted with IGF-1R in HKC-8 cells and liquid chromatography and tandem mass spectrometry (LC-MS/MS) data supported the concept that IGF-1R is one of the HRD1 substrates. HRD1 promoted the IGF-1R ubiquitination for degradation in HKC-8 cells, and the down-regulation of HRD1 reversed the protective effects of RESV in HKC-8 cells. In summary, we have demonstrated that RESV reduces proteinuria and attenuates the progression of renal fibrosis in db/db mice. These protective effects of RESV on DN were associated with the up-regulation of HRD1, induced by RESV, and the promotion of IGF-1R ubiquitination and degradation.