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

Yanli Cheng; Jingjing Zhang; Weiying Guo; Fengsheng Li; Weixia Sun; Jing Chen; Chi Zhang; Xuemian Lu; Yi Tan; Wenke Feng; Yaowen Fu; Gilbert C Liu; Zhonggao Xu; Lu Cai

doi:10.1016/j.freeradbiomed.2016.02.002

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

Free Radic Biol Med. 2016 Apr:93:94-109. doi: 10.1016/j.freeradbiomed.2016.02.002. Epub 2016 Feb 2.

Authors

Yanli Cheng¹, Jingjing Zhang², Weiying Guo³, Fengsheng Li⁴, Weixia Sun³, Jing Chen⁵, Chi Zhang⁶, Xuemian Lu⁷, Yi Tan⁸, Wenke Feng⁹, Yaowen Fu³, Gilbert C Liu¹⁰, Zhonggao Xu¹¹, Lu Cai¹²

Affiliations

¹ 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.
² 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.
³ The First Hospital of Jilin University, Changchun 130021, China.
⁴ The Second Artillery General Hospital, Beijing 100088, China.
⁵ Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA.
⁶ 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.
⁷ The Third Affiliated Hospital of the Wenzhou Medical University, Ruian 325200, China.
⁸ 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.
⁹ Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA; Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
¹⁰ Child and Adolescent Health Research Design and Support, University of Louisville, Louisville, KY 40204, USA.
¹¹ The First Hospital of Jilin University, Changchun 130021, China. Electronic address: renalxu@163.com.
¹² 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.

PMID: 26849944
PMCID: PMC7446394
DOI: 10.1016/j.freeradbiomed.2016.02.002

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.

Keywords: Antioxidants; Diabetic nephropathy; FGF21; Nrf2; Oxidative stress; PPARα agonist; Type 1 diabetes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
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
Fenofibrate / administration & dosage*
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
Oxidative Stress / drug effects
PPAR alpha / agonists
PPAR alpha / genetics
Signal Transduction / drug effects

Substances

NF-E2-Related Factor 2
Nfe2l2 protein, mouse
PPAR alpha
fibroblast growth factor 21
Fibroblast Growth Factors
Fenofibrate

Abstract

Publication types

MeSH terms

Substances

Grants and funding