الفهرس 
Kidney
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Abstract
Nephrotoxicity is considered as a type of acute kidney injury (AKI) which is characterized by a rapid loss of renal function due to acute and severe damage to the kidney. It occurs due to poisonous effect of some toxic chemicals and certain drugs on the kidney. Gentamicin is the most nephrotoxic aminoglycoside antibiotic and is frequently used as a first and second choice drug in a vast variety of clinical situations that are caused by bacteria and infections of the blood, abdomen, lungs, skin and bones. The current study aimed to investigate the nephroprotective effects of Febuxostat, Mirtazapine, and their combination against gentamicin-induced nephrotoxicity in rats. Further, the underlying molecular mechanisms will be identified. In the present study, male albino rats (n=8 /group) were divided in to seven groups, the first two groups served as negative control and gentamicin control (100 mg/ kg, I.P., daily for 7 consecutive days). Then rats were P.O. administered with febuxostat (5, 10 mg/kg), mirtazapine (15, 30 mg/kg) and combination of Mirtazapine (30 mg/kg) and Febuxostat (10 mg/kg) daily for 14 days, then concomitantly with gentamicin for additional 7 days. Serum was collected for biochemical determination of blood urea nitrogen and serum creatinine. Kidney tissues were used for biochemical determination of: superoxide dismutase (SOD) enzyme activity, glutathione peroxidase (GSH-Px) enzyme activity, lipid peroxides (measured as MDA) content, tumor necrosis factor –alpha (TNF-α) content, extracellular signal-regulated protein kinase 1/2 (ERK1/2) content, monocyte chemoattractant protein (MCP-1) gene expression and nuclear factor-kappa B (NF-κB) gene expression. Also, histopathological examination and immunohistochemical staining of caspase-3 were carried out. Treatment of nephrotoxic rats with Febuxostat (5mg/kg, 10mg/kg) or mirtazapine (15, 30 mg/kg) caused a significant (p<0.05) decrease in serum creatinine and BUN level, renal MDA, TNF-α and ERK1/2 contents, expression of both MCP-1 and NF-κB compared to gentamicin group. On the other hand, there were significant (p<0.05) increase in both SOD and GPx enzyme activities. Treatment of nephrotoxic rats with a combination of Febuxostat (10mg/kg) and Mirtazapine (30mg/kg) caused a significant (p<0.05) increase in GPx enzyme activity compared to Febuxostat (10mg/kg) and Mirtazapine (30mg/kg) groups. On the other hand, it caused a significant (p<0.05) decrease in renal TNF-α content and in expression of NF-κB compared to Febuxostat (10mg/kg) and Mirtazapine (30mg/kg) groups. Marked improvement of histological features and superior anti-apoptotic effect is noticed in kidney sections from rats treated with combination group. These findings revealed that both Febuxostat and Mirtazapine alleviated gentamicin-induced nephrotoxicity due to antioxidant, antiinflammatory and antiapoptotic effects and also, showed that combination therapy was able to ameliorate progression of nephrotoxicity and enhance anti-inflammatory and antioxidant effects. Key words: ERK1/2; Febuxostat; Gentamicin; Mirtazapine; Nephrotoxicity; TNF-α