Nicorandil prevents the nephrotoxic effect of cyclosporine-A in albino rats through modulation of HIF-1α/VEGF/eNOS signaling

Abstract

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.

Extracellular cyclophilins A and C induce dysfunction of pancreatic microendothelial cells

“…In this case, LPS did not affect eNOS activation, however, treatment with 0.2 μM CsA alone decreased the enzyme activation (Figures 4A,B). This effect of CsA on eNOS activity has been previously reported and is related to the effects of the drug on intracellular pathways (Arab et al, 2021;Harb et al, 2021). eCypA also reduced eNOS phosphorylation, showing levels of 33.0 ± 10.4% (p < 0.01).…”

Nicorandil ameliorates gentamicin-induced nephrotoxicity through Nrf2/HO-1, p38 MAPK/NF-κB p65/NO and miR-7/CHOP pathways

“…In contrast, NR treatment reversed the impact of GM on NO production as well as eNOS expression 51 . Recently, NR has been reported to increase eNOS protein expression in bleomycininduced pulmonary fibrosis 52 , as well as nephrotoxic model of cyclosporine-A in rats 23 . Interestingly, it has been demonstrated that NR has the ability to enhance the expression eNOS in cardiac tissue via activation of an ATP-dependent K channel 44 .…”

“…Regarding the renal effect of NR, it was reported to protect podocytes from hyperglycemia-induced oxidative stress 13 and ameliorated renal injury induced by unilateral ureteral obstruction in rats 22 . Recently, NR was shown to prevent the deleterious effects of cyclosporine-A in the kidney via modulation of HIF-1α/VEGF/eNOS signaling 23 . However, the nephroprotective effect of NR against GM-induced renal toxicity has not been yet clarified.…”

Necrostatin‐1 mitigates renal ischaemia–reperfusion injury ‐ time dependent ‐ via aborting the interacting protein kinase (RIPK‐1)‐induced inflammatory immune response

“…C Cr was calculated using the previously documented formula 36 …”