Renoprotective Effects of Fenofibrate via Modulation of LKB1/AMPK mRNA Expression and Endothelial Dysfunction in a Rat Model of Diabetic Nephropathy

Abstract

This study was conducted to investigate whether the renoprotective effects of fenofibrate are mediated via attenuation of endothelial dysfunction and modulating the mRNA expression of adenosine monophosphate-activated protein kinase (AMPK) and its downstream kinase liver kinase B1 (LKB1) in rats with diabetic nephropathy (DN).Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg kg^-1). Fenofibrate (100 mg kg^-1, p.o.) was given to diabetic rats daily for 12 weeks. Treatment with fenofibrate significantly improved the renal function as revealed by the significant reductions in urinary albumin excretion and serum levels of creatinine and urea, in addition to the significant increase in creatinine clearance compared with the diabetic control group. Hyperglycemia-induced oxidative damage was ameliorated by treatment with fenofibrate as indicated by the significantly increased levels of glutathione and catalase together with the significant decrease in lipid peroxidation. Administration of fenofibrate caused significant increases in renal nitric oxide (NO) production and mRNA expression of endothelial NO synthase (eNOS), AMPK and LKB1, reflecting improvement of endothelial function. Our results give further insights into the mechanisms underlying the protective role of fenofibrate in DN via modulation of AMPK, LKB1 and eNOS mRNA expression.

Diabetic nephropathy: Is there a role for oxidative stress?

“…AMPK activation promotes mitochondrial substrate utilisation and ATP generation, in parallel with stimulation of antioxidant gene expression to ensure an optimal redox balance [123]. In diabetes, AMPK is downregulated in the kidney and associated with impaired mitochondrial function [124] and reduced AMPK-mediated inhibition of NADPH oxidase (Nox2) resulting in increased oxidant species production [85,125]; upregulation/activation of AMPK has been proposed as a potential therapeutic intervention in the diabetic kidney [126].…”

Diabetic Nephropathy: Perspective on Novel Molecular Mechanisms

“…Reduced AMPK, as seen in the diabetic kidney of both rodents and humans [65], is associated with reduced catabolic activity (mitochondrial function) [65], and reduced AMPK-mediated inhibition of NADPH oxidase (Nox2) resulting in increased ROS production [71,72]. Taken together, these results suggest that, in the diabetic kidney, upregulation of AMPK could be therapeutically beneficial in DN [73] to regulate nutrient utilisation and mitochondrial function towards maintenance of an optimum redox balance.…”

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

“…Because partial renal protection by FF ( Figures 5C, 6) remained in Akt2-KO mice, we further showed that FF also stimulates AMP-activated protein kinase (AMPK)-mediated renal protection in T1D-associated DN (Figures 7). In addition, although we showed that AMPKα was activated using a phospho-specific antibody, but we were unable to conclude that FF-activated renal protection was AMPKα-dependent because we did not examine other AMPK isoforms, although in previous reports describing FF activation of AMPK [25][26][27] , only couple of them directly or indirectly measured AMPKα induction by FF and hardly any mentioned AMPK isoforms [25][26][27] .…”

“…In the current study (Figure 8), we propose that AMPK is partially responsible for the FGF21-mediated renal protection from HG because the use of an AMPK inhibitor alongside Akt2-siRNA silencing abolished the preventive effect of FF on the HG-induced phenotype of HK-2 cells. In fact, Al-Rasheed et al have previously described the involvement of the activation of liver kinase B1/AMPK in the FF-induced protection against DN in T1D rats [27] . Although we and others have not determined how FGF21 activates AMPK in T1D mice and rats [27] , there is convincing evidence that FGF21 activates the AMPK pathway, either directly through fibroblast growth factor receptor 1/β-klotho signaling, or indirectly by stimulating the secretion of adiponectin and corticosteroids, which can activate AMPK signaling in their target tissues [43] .…”

“…In fact, Al-Rasheed et al have previously described the involvement of the activation of liver kinase B1/AMPK in the FF-induced protection against DN in T1D rats [27] . Although we and others have not determined how FGF21 activates AMPK in T1D mice and rats [27] , there is convincing evidence that FGF21 activates the AMPK pathway, either directly through fibroblast growth factor receptor 1/β-klotho signaling, or indirectly by stimulating the secretion of adiponectin and corticosteroids, which can activate AMPK signaling in their target tissues [43] . Therefore, FF protects against T1D-induced DN via a PPARα-mediated increase in FGF21, which activates Akt2/GSK-3β/Fyn/Nrf2 signaling to upregulate the Nrf2-mediated antioxidant mechanism, but also via activation of AMPK, which mediates an amelioration of the metabolic defects.…”