Renoprotective impact of tiron against diclofenac-induced nephrotoxicity: targeting TLR4/NF-κB/NLRP3/Caspase-1/IL1-β pathway.

Nephrotoxicity is a documented side effect of non-steroidal anti-inflammatory drugs (NSAIDs) like diclofenac (Diclo). Thus, this study was executed to assess the renoprotective effect of tiron against Diclo-induced nephrotoxicity. Nephrotoxicity was induced in mice by single administration of Diclo (300 mg/kg, po). Mice received tiron (140 and 280 mg/kg, ip) for 7 successive days, Diclo was administered on day 7 after 1 h of tiron injection. Diclo significantly deteriorated kidney function and structure; Diclo injection produced a marked increase in serum levels of creatinine, urea and blood urea nitrogen (BUN) as well as profound escalation in levels of creatinine, total protein and albumin in urine. Moreover, Diclo induced oxidative stress manifested by substantial increase in malondialdehyde (MDA) and notable decrease in reduced glutathione (GSH) level and superoxide dismutase (SOD) activity. Additionally, Diclo significantly increased renal levels of toll-like receptor 4 (TLR-4), nuclear factor kappa B (NF-κB), NOD-like receptor protein 3 (NLRP3), apoptosis associated speck-like protein, Caspase-1 and interleukin (IL)-1β, besides elevation in renal expression of cyclooxygenase (COX)-II. The results of these biomarkers were further confirmed by histopathological analysis. Injection of tiron in both doses markedly improved Diclo-induced alterations. Hence, tiron could be a promising candidate in alleviating nephrotoxicity induced by NSAIDs following further clinical research.