title: HRD1-Mediated IGF-1R Ubiquitination Contributes to Renal Protection of Resveratrol in db/db Mice.
abstract: 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), α-smooth muscle actin (α-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.
authors.affiliation: Department of Endocrinology (C.Y.), Clinical Medical College of Yangzhou University, Yangzhou 225001, Jiangsu, China; Jiangsu Key Laboratory of Xenotransplantation (C.Y., W.X., Y.H., M.L., Y.S., H.Y., X.L.), Department of Pathophysiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. and Renal Division (W.X.), Zhuji People Hospital, Zhuji 311800, Zhejiang, China.
authors.forename: Caifeng
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Endocrinology (C.Y.), Clinical Medical College of Yangzhou University, Yangzhou 225001, Jiangsu, China; Jiangsu Key Laboratory of Xenotransplantation (C.Y., W.X., Y.H., M.L., Y.S., H.Y., X.L.), Department of Pathophysiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. and Renal Division (W.X.), Zhuji People Hospital, Zhuji 311800, Zhejiang, China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Endocrinology (C.Y.), Clinical Medical College of Yangzhou University, Yangzhou 225001, Jiangsu, China; Jiangsu Key Laboratory of Xenotransplantation (C.Y., W.X., Y.H., M.L., Y.S., H.Y., X.L.), Department of Pathophysiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. and Renal Division (W.X.), Zhuji People Hospital, Zhuji 311800, Zhejiang, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Endocrinology (C.Y.), Clinical Medical College of Yangzhou University, Yangzhou 225001, Jiangsu, China; Jiangsu Key Laboratory of Xenotransplantation (C.Y., W.X., Y.H., M.L., Y.S., H.Y., X.L.), Department of Pathophysiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. and Renal Division (W.X.), Zhuji People Hospital, Zhuji 311800, Zhejiang, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Endocrinology (C.Y.), Clinical Medical College of Yangzhou University, Yangzhou 225001, Jiangsu, China; Jiangsu Key Laboratory of Xenotransplantation (C.Y., W.X., Y.H., M.L., Y.S., H.Y., X.L.), Department of Pathophysiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. and Renal Division (W.X.), Zhuji People Hospital, Zhuji 311800, Zhejiang, China.
authors.forename: Yachen
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Endocrinology (C.Y.), Clinical Medical College of Yangzhou University, Yangzhou 225001, Jiangsu, China; Jiangsu Key Laboratory of Xenotransplantation (C.Y., W.X., Y.H., M.L., Y.S., H.Y., X.L.), Department of Pathophysiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. and Renal Division (W.X.), Zhuji People Hospital, Zhuji 311800, Zhejiang, China.
authors.forename: Hui
authors.initials: H
authors.lastname: You
authors.affiliation: Department of Endocrinology (C.Y.), Clinical Medical College of Yangzhou University, Yangzhou 225001, Jiangsu, China; Jiangsu Key Laboratory of Xenotransplantation (C.Y., W.X., Y.H., M.L., Y.S., H.Y., X.L.), Department of Pathophysiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. and Renal Division (W.X.), Zhuji People Hospital, Zhuji 311800, Zhejiang, China.
authors.forename: Xiubin
authors.initials: X
authors.lastname: Liang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D002853:Chromatography, Liquid; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*; D053719:Tandem Mass Spectrometry; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D015415:Biomarkers; D020011:Protective Agents; D012333:RNA, Messenger; D013267:Stilbenes; D016212:Transforming Growth Factor beta; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D017526:Receptor, IGF Type 1; D000077185:Resveratrol