Hesperetin ameliorates diabetic nephropathy in rats by activating Nrf2/ARE/glyoxalase 1 pathway

• Published in: Biomedicine & pharmacotherapy 2019-03, Vol.111, p.1166-1175
• Main Authors: Chen, Ya-Jing, Kong, Li, Tang, Zhuang-Zhuang, Zhang, Yu-Meng, Liu, Yue, Wang, Tao-Yun, Liu, Yao-Wu
• Format: Article
• Language: English
• Subjects: AGEs/RAGE axis; Animals; Carboxylic Ester Hydrolases - metabolism; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - etiology; Diabetic Nephropathies - metabolism; Diabetic nephropathy; Glutamate-Cysteine Ligase - metabolism; Glycation End Products, Advanced - metabolism; Glyoxalase 1; Hesperetin; Hesperidin - pharmacology; Inflammation - drug therapy; Inflammation - metabolism; Kidney - drug effects; Kidney - metabolism; Lactoylglutathione Lyase - metabolism; Male; NF-E2-Related Factor 2 - metabolism; Nrf2/ARE pathway; Protective Agents - pharmacology; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Streptozocin - pharmacology; Up-Regulation - drug effects
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.01.030

[Display omitted] •Hesperetin could attenuate diabetic nephropathy.•Enhancement of glyoxalase 1 contributed to the beneficial effects.•Activation of Nrf2/ARE pathway was involved in glyoxalase 1 enhancement. Diabetic nephropathy (DN) is one of the most common diabetic complications, and alpha-carbonyl aldehydes and their detoxicating enzyme glyoxalase 1 (Glo-1) play vital roles in pathogenesis of diabetic complications. The aim of this study was to evaluate the renoprotective effects of hesperetin against DN in rats, and to investigate mechanisms from the aspect of Nrf2/ARE/Glo-1 pathway. Streptozotocin-induced diabetic rats were treated orally with hesperetin (50 and 150 mg/kg), or nuclear factor erythroid-derived-2-like 2 (Nrf2) inducer tert-butylhydroquinone (tBHQ, 25 mg/kg) for 10 weeks. Then proteinuria, creatinine, urea nitrogen, and uric acid were assayed for renal functions, fibronectin and collagen IV levels by immunohistochemistry, as well as periodic acid-Schiff staining and electron microscope observation, were used to assess renal morphology. Glo-1 activity, protein, and mRNA levels and the classic Nrf2/ARE pathway were investigated. Moreover, advanced glycation endproducts (AGEs) and its receptor RAGE, interleukin-1β and tumor necrosis factor-α levels were also examined in the kidney. Hesperetin markedly ameliorated the renal functions and structural changes of diabetic rats, accompanied by up-regulation of Glo-1 as well as inhibition of AGEs/RAGE axis and inflammation. Meanwhile, hesperetin caused significant increases in Nrf2 and p-Nrf2 levels, as well as up-regulation of γ-glutamylcysteine synthetase, a well-known target gene of Nrf2/ARE signaling. Our results demonstrated that hesperetin could slow down the pathological process of DN, and Glo-1 enhancement contributed to the beneficial effects, which was obtained by the activation of Nrf2/ARE pathway.