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

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

PPAR-α Agonist Fenofibrate Prevented Diabetic Nephropathy by Inhibiting M1 Macrophages via Improving Endothelial Cell Function in db/db Mice

“…PPAR-α agonist fenofibrate is known as an important lipidlowering drugs in clinical. Moreover, PPAR-α agonist fenofibrate has been proven to prevent DN and reduce urinary albumin in diabetic patients (26,27) and in diabetic mice (29)(30)(31)(32), which is independent of the effect on lipid-lowering. In current research, mice in different groups were similar in total cholesterol (TC).…”

“…Furthermore, our previous research also found that fenofibrate reduced microalbuminuria in patients with type 2 diabetes ( 28 ). In addition, PPAR-α agonists have been demonstrated to prevent DN and reduce proteinuria in both type 1 and type 2 diabetic animals ( 29 – 32 ). Nevertheless, the mechanism of how PPAR-α agonist fenofibrate prevents DN has not been fully explored.…”

Fibroblast growth factor 21 is associated with increased serum total antioxidant capacity and oxidized lipoproteins in humans with different stages of chronic kidney disease

“… 57 Unfortunately, the therapeutic potential of FGF21 for OS in CKD in humans has not yet been studied, possibly due to its instability and short half-life. 58 Furthermore, to be able to consider FGF21 as a treatment in CKD, it is necessary to better understand the role of this growth factor in the mechanisms of the disease. The results of this study suggest that serum FGF21 is associated to OS markers in CKD; however, longitudinal studies that allow evaluation of causal associations would bring valuable information in this topic.…”

Tert-butylhydroquinone mitigates Carbon Tetrachloride induced Hepatic Injury in mice

“…Nrf2 is a pivotal factor in oxidative stress response. Increasing evidence showed that Nrf2 displayed cytoprotective effects when cells were exposed adverse condition [31][32][33][34]. Nrf2 regulates ranges of antioxidants gene expression via binding to antioxidant response element.…”