Co-targeting of endothelin-A and vitamin D receptors: a novel strategy to ameliorate cisplatin-induced nephrotoxicity.

BACKGROUND: Although modulation of the vitamin D receptor (VDR) and endothelin-A receptor (ETAR) has previously been reported to offer renoprotection against cisplatin-induced nephrotoxicity, the possible interaction between the ET-1 and vitamin D pathways remains obscure. Therefore, the present study addressed the possible interaction between these signalling pathways using BQ-123 (a selective ETAR blocker) and alfacalcidol (a vitamin D3 analogue) separately or in combination. METHODS: Male Sprague-Dawley rats were divided into the following groups: control (DMSO orally), cisplatin (single dose of 6 mg/kg ip; nephrotoxicity model), cisplatin + BQ-123 (1 mg/kg BQ-123 ip 1 h before and 1 day after cisplatin), cisplatin + alfacalcidol (50 ng/kg alfacalcidol orally 5 days before and 14 days after cisplatin), and cisplatin + BQ-123+alfacalcidol. Nephrotoxicity was evaluated 96 h and 14 days following cisplatin administration. RESULTS: Both BQ-123 and alfacalcidol counteracted cisplatin-induced nephrotoxic changes. Specifically, they reduced serum creatinine and urea levels; renal tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-ß1), and phosphorylated nuclear factor-kappa B (pNF-κB) content; and caspase-3 activity. They downregulated ET-1 and ETAR expression and ameliorated cisplatin-induced acute tubular necrosis. In addition, the treatments have increased VDR and endothelin-B receptor (ETBR) expression; however, BQ-123 did not affect ETBR. The effect of the combination regimen surpassed that of each drug alone. CONCLUSION: These findings highlight the potential cross-talk between vitamin D and ET-1 pathways and pave the way for future preclinical/clinical studies to explore further mechanisms involved in this cross-talk.

Evaluation of l-arginine on kidney function and vascular reactivity following ischemic injury in rats: protective effects and potential interactions.

BACKGROUND: There is an interaction between many cell types involved in the pathophysiology of ischemic acute renal failure. Nitric oxide (NO) precursors, especially l-arginine, may have protective effects on tissue ischemia/reperfusion injury (IRI); however, their molecular mechanisms are unclear. In the present study, the interaction between l-arginine, cyclo-oxygenase (COX)-2 and reactive oxygen species (ROS) in the pathogenesis of ischemic acute renal failure was investigated. METHODS: Ischemia/reperfusion injury model in rats was used and various biochemical parameters examined. The rat isolated aortic rings served as model for hypoxia/reoxygenation where endothelium dependent and independent relaxations were exerted. RESULTS: Pre-treatment of rats subjected to IRI with l-arginine (125mg/kg) significantly reduced kidney MDA levels, elevated kidney SOD activity, GSH level and total NO levels at 24 and 48h after reperfusion. Kidney COX-2 level was only different in the l-arginine-treated group 48h after reperfusion compared to the IRI group. Pre-treatment with l-arginine (10(-2)M) alone or in combination with celecoxib significantly potentiated the acetylcholine (Ach)-induced relaxations in control and hypoxic rings. The effect of the combination was synergistic only in hypoxic rings. Addition of ascorbic acid to the celecoxib-arginine combination did not produce further potentiation. Sodium nitroprusside-induced relaxations in control and hypoxic rings were potentiated by l-arginine or celecoxib-arginine combination but not by ascorbic acid. CONCLUSIONS: The protective effect of l-arginine may result from the interaction between NO and ROS and increased NO bioavailability. The protective effects of combined celecoxib and l-arginine against IRI could be attributed to their antioxidant activity which exceeded that of ascorbic acid.