Despite cyclosporine-A (CsA) is a widely used immunosuppressive drug; its nephrotoxic effect puts a limitation for chronic administration. Herein we tried to investigate its renal effect on endothelial dysfunction targeting the hypoxia-inducible factor (HIF-1α)/vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) pathway and the possible modulation by nicorandil. Eight groups of adult male Wistar rats were included; 1: control, 2: vehicle group (received oil), 3: glibebclamide 5mg/kg/day/orally was administered. 4: group received nicorandil 10mg/kg/day/orally. 5: group received cyclosporine 25mg/kg/day/orally. 6: combined cyclosporine and nicorandil, 7: glibenclamide was added to cyclosporine, and 8: group received both cyclosporine and nicorandil combined with glibenclamid. The treatment continued for 6 weeks. Combined nicorandil with cyclosporine improved renal function deterioration initiated by cyclosporine. Cyclosporine decreased the renal expression levels (P<0.001) of HIF-1α, eNOS, and VEGF inducing endothelial dysfunction and the triggered inflammation, and upregulated the pro-fibrotic marker transforming growth factor (TGF-β). Nicorandil fixed the disturbed HIF-1α/VEGF/eNOS signaling. Nicorandil corrected the renal functions confirmed by improved the histological glomerular tuft retraction that was obvious in the cyclosporine group, without significant influence by glibenclamid. Proper protection from CsA-induced nephrotoxicity was achieved by nicorandil. Nicorandil reversed the disturbed HIF-1α/VEGF/eNOS pathway created by cyclosporine.