Inhibition of p75/p53 axis by ambrisentan suppresses apoptosis and oxidative stress-mediated renal damage in a cisplatin AKI model.

Cisplatin (CP) is a potent antineoplastic agent that triggers nephrotoxicity as a major adverse effect which can cause treatment interruptions and limitations to its clinical use. Nephrotoxicity associated with CP involves inflammation, oxidative stress, and apoptosis in kidney tubules. The objective of this work was to assess the effect of the blockade of endothelin-1 (ET-1) receptor with ambrisentan on altered renal function induced by CP. Swiss albino mice were assigned into control, CP, CP/Amb-5, and CP/Amb-10 groups. Ambrisentan improved kidney function (serum creatinine and BUN) and histopathological changes in comparison to CP-treated group. Ambrisentan significantly reduced protein expression of p75 and protein level of JNK influencing renal apoptosis as evidenced by reducing p53, caspase-3, and Bax levels and elevating Bcl-2 level (p < 0.05 vs CP group). Moreover, vasodilatory effect of ambrisentan was indicated by significant increase in level of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) (p < 0.05 vs CP group). Ambrisentan also significantly restored oxidative balance in renal tissues as evidenced by reduced malondialdehyde and increased total antioxidant capacity and superoxide dismutase activity, in addition to decreasing nitric oxide levels (p < 0.05 vs CP group). This protective effect of ambrisentan might be mediated through the downregulation of death receptor, P75 that in turn restores renal blood flow and oxidative balance and regulates p53, VEGF/eNOS, NF-κB, and Bcl-2/Bax/caspase-3 signaling.