Fumarate ameliorated doxorubicin-induced nephrotoxicity: The role of pro-inflammatory cytokines and endothelial nitric oxide synthase signaling pathway

Purpose: Nephrotoxicity is a deleterious effect of doxorubicin (dox). This study investigated the renoprotective property of the tricarboxylic acid cycle metabolite, fumarate, in dox-induced nephrotoxicity. Methods: Male Wistar rats were randomly divided into four groups containing eight animals each; I: distilled water (10 ml/kg, po), II: dox (10 mg/kg stat. ip), III: dox (10 mg/kg, ip) + fumarate (50 mg/kg, po) and IV: dox (10 mg/kg, ip) + fumarate (100 mg/kg, po). The animals were treated for 10 days and euthanised on the last day. The kidneys were excised and immediately frozen for molecular analysis. A kidney section was fixed in formalin + saline solution for the histological assay. Results: Fumarate at 50 mg/kg caused a 23. 2 %, p<0.01 reduction in kidney injury molecule (KIM) expression in dox-treated rats. There was a reduction in the expression of interleukin (IL)-1β expression in nephrotoxic rats at 100 mg/kg of fumarate, (32.4±0.6 vs 28.5±0.0, p<0.05). Similarly, IL-6 expression was decreased in a dose-dependent manner in dox-treated rats. The initial fall in superoxide dismutase (SOD) activity at 50 mg/kg of fumarate was reversed at 100 mg/kg (27.7±0.9 vs 28.6±0.4, p>0.05) in rats treated with dox. Endothelial nitric oxide synthase (eNOS) expression was significantly reduced in fumarate-treated dox rats at 50 mg/kg only, (27.1±0.7 vs 23.2±0.7, p<0.05). Histological sectioning of the kidney revealed distortions in the glomerulus of dox-treated rats and fumarate reversed these changes. Conclusion: Data from this study show that fumarate ameliorated dox-induced nephrotoxicity by reducing eNOS and cytokine signaling.