Synergistic Reno-Protective Effects of Valproate Sodium and Metformin in Diabetic Nephropathy Mice Model Through Attenuating the Expression of Pro-Inflammatory and Enhancing the Expression of Sirt-1 and Bcl-2
Abstract
Background: Diabetes is the most common metabolic disease resulting from a relative deficiency of insulin secretionor action. This study aimed to evaluate the synergistic inhibitory effects of valproate sodium (VPS) and metformin(MET) on alloxan-induced diabetic nephropathy and to understand the mechanism of their effect on the expressionpathway of inflammatory genes, Sirt-1 and Bcl-2.
Methods: Female mice (C57BL/6) were induced to have diabetes by intraperitoneal injection of a single dose of alloxan(120 mg/kg). Diabetic mice were treated with three doses of sodium valproate (10, 20, and 40 mg/kg) and a single doseof metformin (200 mg/kg) for a period of 28 days. The expression of inflammatory genes and histological changes in thekidneys of the mice were evaluated for a period of 28 days.
Results: The hyperglycemia induced by alloxan-induced diabetes was significantly reduced after a 28-day course ofvalproate sodium administration (P < 0.05). Combined treatment of sodium valproate with metformin significantlyreduced the expression of inflammatory genes in the kidney tissue of diabetic mice. A significant increase in theexpression of Sirt-1 and Bcl2 was observed in diabetic mice receiving valproate sodium and metformin compared to thediabetic group. Treatment of diabetic mice with valproate sodium and metformin prevented the adverse histopathologicalchanges caused by renal nephropathy, which was accompanied by normal glomerular capillary size and reduceddilatation of the urinary tract compared to diabetic mice.
Conclusion: It can be concluded that MET and VPS in combination can prevent alloxan-induced diabetic nephropathythrough attenuating inflammatory pathways and decreasing inflammatory genes expressions together probably with thesuppression of oxidative stress, inflammation and apoptosis.
