Journal
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
Volume 99, Issue 4, Pages 411-417Publisher
CANADIAN SCIENCE PUBLISHING
DOI: 10.1139/cjpp-2020-0012
Keywords
nephrotoxic; cyclosporine-A; nicorandil; HIF-1 alpha/VEGF/eNOS
Categories
Funding
- Deanship of Scientific Research at King Khalid University [GRP-117-41]
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This study demonstrated that the combination of nicorandil with CsA improved renal function deterioration caused by CsA and restored the disturbed HIF-1 alpha/VEGF/eNOS pathway.
Despite that cyclosporine-A (CsA) is a widely used immunosuppressive drug, its nephrotoxic effect limits its long-term administration. Herein we tried to investigate its renal effect on endothelial dysfunction targeting the hypoxia-inducible factor (HIF-1 alpha) / 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) glibenclamide 5 mg.kg(-1).day(-1) administered orally; (4) nicorandil 10 mg.kg(-1).day(-1) administered orally; (5) CsA 25 mg.kg(-1).day(-1) administered orally; (6) combined administration of CsA and nicorandil; (7) glibenclamide was added to CsA; and (8) both CsA and nicorandil were combined with glibenclamide. The treatment continued for six weeks. Combined nicorandil with CsA improved renal function deterioration initiated by CsA. CsA decreased the renal expression levels (P < 0.001) of HIF-1 alpha, eNOS, and VEGF, inducing endothelial dysfunction and triggering inflammation, and upregulated the profibrotic marker transforming growth factor (TGF-beta). Nicorandil fixed the disturbed HIF-1 alpha/VEGF/eNOS signaling. Nicorandil corrected the renal functions, confirmed by the improved histological glomerular tuft retraction that was obvious in the CsA group, without significant influence by glibenclamide. Proper protection from CsA-induced nephrotoxicity was achieved by nicorandil. Nicorandil reversed the disturbed HIF-1 alpha/VEGF/eNOS pathway created by CsA.
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