Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy

• Published in: Free radical biology & medicine 2016-04, Vol.93, p.94-109
• Main Authors: Cheng, Yanli, Zhang, Jingjing, Guo, Weiying, Li, Fengsheng, Sun, Weixia, Chen, Jing, Zhang, Chi, Lu, Xuemian, Tan, Yi, Feng, Wenke, Fu, Yaowen, Liu, Gilbert C., Xu, Zhonggao, Cai, Lu
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Apoptosis - drug effects; Diabetes Complications - drug therapy; Diabetes Complications - genetics; Diabetes Complications - pathology; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - genetics; Diabetic Nephropathies - pathology; Diabetic nephropathy; Fenofibrate - administration & dosage; FGF21; Fibroblast Growth Factors - biosynthesis; Fibroblast Growth Factors - genetics; Gene Expression Regulation - drug effects; Humans; Mice; NF-E2-Related Factor 2 - biosynthesis; NF-E2-Related Factor 2 - genetics; Nrf2; Oxidative stress; Oxidative Stress - drug effects; PPAR alpha - agonists; PPAR alpha - genetics; PPARα agonist; Signal Transduction - drug effects; Type 1 diabetes
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2016.02.002

The lipid lowering medication, fenofibrate (FF), is a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, possessing beneficial effects for type 2 diabetic nephropathy (DN). We investigated whether FF can prevent the development of type 1 DN, and the underlying mechanisms. Diabetes was induced by a single intraperitoneal injection of streptozotocin in C57BL/6J mice. Mice were treated with oral gavage of FF at 100mg/kg every other day for 3 and 6 months. Diabetes-induced renal oxidative stress, inflammation, apoptosis, lipid and collagen accumulation, and renal dysfunction were accompanied by significant decrease in PI3K, Akt, and GSK-3β phosphorylation as well as an increase in the nuclear accumulation of Fyn [a negative regulator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)]. All these adverse effects were significantly attenuated by FF treatment. FF also significantly increased fibroblast growth factor 21 (FGF21) expression and enhanced Nrf2 function in diabetic and non-diabetic kidneys. Moreover, FF-induced amelioration of diabetic renal damage, including the stimulation of PI3K/Akt/GSK-3β/Fyn pathway and the enhancement of Nrf2 function were abolished in FGF21-null mice, confirming the critical role of FGF21 in FF-induced renal protection. These results suggest for the first time that FF prevents the development of DN via up-regulating FGF21 and stimulating PI3K/Akt/GSK-3β/Fyn-mediated activation of the Nrf2 pathway. [Display omitted] •The first study on the prevention by fenofibrate (FF) of type 1 diabetic nephropathy (DN).•The protective effect of FF on diabetes-induced renal damage is mediated by FGF21.•FGF21-mediated up-regulating Nrf2 function assists in the prevention of DN.•Activating Nrf2 function by FGF21 is due to PI3K/Akt/GSK-3β/Fyn pathway stimulation.