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Int J Biol Sci. 2020 Jan 1;16(4):553-567. doi: 10.7150/ijbs.40643. eCollection 2020.

The Role of Akt2 in the Protective Effect of Fenofibrate against Diabetic Nephropathy.

Author information

1
Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
2
Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China.
3
Department of Microbiology and Immunology, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, China.
4
Pediatric Research Institute, Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA.

Abstract

Fenofibrate (FF) protects against diabetic nephropathy (DN) in type 1 diabetic (T1D) mice by upregulating the expression of fibroblast growth factor 21 (FGF21), leading to the activation of the Akt-mediated Nrf2 antioxidant pathways. Here, we examined which isoforms of Akt contribute to FF activation of FGF21-mediated renal protection by examining the phosphorylation and expression of three isoforms, Akt1, Akt2, and Akt3. T1D induced by a single intraperitoneal dose of streptozotocin (STZ) resulted in reduced phosphorylation of one isoform, Akt2, but FF treatment increased renal Akt2 phosphorylation in these and normal mice, suggesting a potential and specific role for renal Akt2 in FF protection against T1D. This was further confirmed using in vitro cultured HK-2 human kidney tubule cells exposed to high glucose (HG) with siRNA silencing of the Akt2 gene and STZ-induced diabetic Akt2-knockout mice with and without 3-month FF treatment. In normal HK-2 cells exposed to HG for 24 hours, FF completely prevented cell death, reduced total Akt expression and glycogen synthase kinase (GSK)-3β phosphorylation, increased nuclear accumulation of Fyn, and reduced nuclear Nrf2 levels. These positive effects of FF were partially abolished by silencing Akt2 expression. Similarly, FF abolished T1D-induced renal oxidative stress, inflammation, and renal dysfunction in wild-type mice, but was only partially effective in Akt2-KO mice. Furthermore, FF treatment stimulated phosphorylation of AMPKα, an important lipid metabolism mediator, which in parallel with Akt2 plays an important role in FF protection against HG-induced HK-2 cells oxidative stress and damage. These results suggest that FF protects against DN through FGF21 to activate both Akt2/GSK-3β/Fyn/Nrf2 antioxidants and the AMPK pathway. Therefore, FF could be repurposed for the prevention of DN in T1D patients.

KEYWORDS:

Akt2, fibroblast growth factor 21; diabetic nephropathy; nuclear factor erythroid 2-related factor 2; peroxisome proliferator-activated receptor α agonist.

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