Sodium nitroprusside improves ischemia-induced neovascularization via the HO-1/NOX and AKT/eNOS signaling pathways in chronic kidney disease.

AIMS: In chronic kidney disease (CKD), the incidence of peripheral arterial disease is elevated and is a major source of morbidity and mortality. Accumulated circulating uremic toxins, particularly asymmetric dimethylarginine (ADMA) and indoxyl sulfate (IS), are shown to increase oxidative stress and reduce nitric oxide bioavailability and generation, ultimately leading to vascular endothelial cell damage. We tested the hypothesis that sodium nitroprusside (SNP) could enhance ischemia-induced neovasculogenesis in CKD and investigated the mechanism behind this effect.

MATERIALS AND METHODS: Mouse models of subtotal nephrectomy-induced CKD and unilateral hindlimb ischemia surgery were created to mimic clinical CKD and peripheral arterial disease, respectively. Primary human aortic endothelial cells were used for in vitro experiments and exposed to ADMA or IS stimulation.

KEY FINDINGS: The SNP treatment upregulated circulating pro-angiogenic factors, improved blood flow recovery, increased capillary density, and reversed the expression level of pro-angiogenic and inflammatory proteins in the ischemic tissues but did not recover renal function in CKD mice. In the in vitro experiment on ADMA- or IS-stimulated human aortic endothelial cells, treatment with SNP enhanced cell viability, improved tube formation and cell migration, reduced reactive oxygen species production, increased pro-angiogenic factors, and decreased inflammatory proteins via the hemeoxygenase-1/NADPH oxidase and AKT/endothelial nitric oxide synthase signaling pathways.

SIGNIFICANCE: Although further clinical studies are needed, this study highlights a theoretical basis for potential therapeutic interventions with SNP in CKD patients who also have vascular complications.