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

Research output: Contribution to journalArticle

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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 100 mg/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.

Original languageEnglish (US)
Pages (from-to)94-109
Number of pages16
JournalFree Radical Biology and Medicine
Volume93
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Fingerprint

Fenofibrate
Diabetic Nephropathies
Up-Regulation
Glycogen Synthase Kinase 3
Kidney
Phosphatidylinositol 3-Kinases
Medical problems
Lipids
PPAR alpha
Phosphorylation
Oxidative stress
fibroblast growth factor 21
Streptozocin
Intraperitoneal Injections
Inbred C57BL Mouse
Oxidative Stress
Collagen
Chemical activation
Apoptosis
Inflammation

Keywords

  • Antioxidants
  • Diabetic nephropathy
  • FGF21
  • Nrf2
  • Oxidative stress
  • PPARα agonist
  • Type 1 diabetes

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

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

In: Free Radical Biology and Medicine, Vol. 93, 01.04.2016, p. 94-109.

Research output: Contribution to journalArticle

Cheng, Y, Zhang, J, Guo, W, Li, F, Sun, W, Chen, J, Zhang, C, Lu, X, Tan, Y, Feng, W, Fu, Y, Liu, GC, Xu, Z & Cai, L 2016, 'Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy', Free Radical Biology and Medicine, vol. 93, pp. 94-109. https://doi.org/10.1016/j.freeradbiomed.2016.02.002
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. / Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy. In: Free Radical Biology and Medicine. 2016 ; Vol. 93. pp. 94-109.
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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 100 mg/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.",
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AU - Cheng, Yanli

AU - Zhang, Jingjing

AU - Guo, Weiying

AU - Li, Fengsheng

AU - Sun, Weixia

AU - Chen, Jing

AU - Zhang, Chi

AU - Lu, Xuemian

AU - Tan, Yi

AU - Feng, Wenke

AU - Fu, Yaowen

AU - Liu, Gilbert C.

AU - Xu, Zhonggao

AU - Cai, Lu

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AB - 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 100 mg/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.

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