In spite of being one of the most powerful anti-cancer drug, the nephrotoxicity of Vincristine (VCR) is not well established in either animals or humans. Hence, this study evaluates the nephrotoxic effect of VCR in rats after sub-chronic long-term administration. Rats were divided into 2 groups (n=10/group) of either control and VCR treated rats (50 mg/kg). Treatments were carried out for 30 consecutive days, after which a series of biochemical and molecular experiments related to kidney function were evaluated. VCR administration significantly decreased the survival rate (69.8 %) and impaired renal function as evidenced by lowered creatinine (Cr) clearance (Ccr), high serum levels of urea and Cr, increased urinary protein levels and resulted in sever cortex pathological alterations, including glomerulus congestion and damage as well as vascular degenerations up to necrosis of both proximal and distal convoluted tubules. Mechanistically, VCR lowered renal antioxidant potential and ATP levels, enhanced lipid peroxidation and induced inflammation. In addition, VCR induced activation of Raf-1-MEK1/2-ERK1/2 signaling pathway leading to downregulation of Bcl- 2 and upregulation of P53, Bax, and cleaved caspase-3. In conclusion, these findings show a nephrotoxic effect of VCR sulfate in rats after sub-chronic administration and such effect was mediated by activation of ERK1/2 induced apoptosis.
KEY WORDS: Vincristine; Nephrotoxicity; Oxidative stress; Apoptosis; Rats.