title: Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy.
abstract: 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.
authors: The First Hospital of Jilin University, Changchun 130021, China; The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou 325035, China; Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA.
authors: Yanli
authors: Y
authors: Cheng
authors: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA; Department of Cardiology at the First Hospital of China Medical University, Shenyang 110016, China; Department of Cardiology at the People's Hospital of Liaoning Province, Shenyang 110016, China.
authors: Jingjing
authors: J
authors: Zhang
authors: The First Hospital of Jilin University, Changchun 130021, China.
authors: Weiying
authors: W
authors: Guo
authors: The Second Artillery General Hospital, Beijing 100088, China.
authors: Fengsheng
authors: F
authors: Li
authors: The First Hospital of Jilin University, Changchun 130021, China.
authors: Weixia
authors: W
authors: Sun
authors: Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA.
authors: Jing
authors: J
authors: Chen
authors: The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou 325035, China; The Third Affiliated Hospital of the Wenzhou Medical University, Ruian 325200, China.
authors: Chi
authors: C
authors: Zhang
authors: The Third Affiliated Hospital of the Wenzhou Medical University, Ruian 325200, China.
authors: Xuemian
authors: X
authors: Lu
authors: The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou 325035, China; Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA; The Third Affiliated Hospital of the Wenzhou Medical University, Ruian 325200, China; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
authors: Yi
authors: Y
authors: Tan
authors: Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
authors: Wenke
authors: W
authors: Feng
authors: The First Hospital of Jilin University, Changchun 130021, China.
authors: Yaowen
authors: Y
authors: Fu
authors: Child and Adolescent Health Research Design and Support, University of Louisville, Louisville, KY 40204, USA.
authors: Gilbert C
authors: GC
authors: Liu
authors: The First Hospital of Jilin University, Changchun 130021, China. Electronic address: renalxu@163.com.
authors: Zhonggao
authors: Z
authors: Xu
authors: The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou 325035, China; Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA; The Third Affiliated Hospital of the Wenzhou Medical University, Ruian 325200, China; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA. Electronic address: L0cai001@louisville.edu.
authors: Lu
authors: L
authors: Cai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048909:Diabetes Complications / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011345:Fenofibrate / Q000008:administration & dosage*; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D047493:PPAR alpha; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D011345:Fenofibrate
keywords: Antioxidants; Diabetic nephropathy; FGF21; Nrf2; Oxidative stress; PPARα agonist; Type 1 diabetes