Indoxyl sulfate impairs valsartan-induced neovascularization
Journal
Redox Biology
Journal Volume
30
Pages
101433
Date Issued
2020
Author(s)
Abstract
Studies revealed that the use of renin-angiotensin-aldosterone system antagonism is not associated with a statistically significant reduction in the risk of cardiovascular events in patients with chronic kidney disease (CKD) compared with that in the general population. We tested the hypothesis that indoxyl sulfate (IS) can interfere with the protective effect of valsartan-mediated on endothelial function in vitro and neovascularization in mice underwent subtotal nephrectomy. In human aortic endothelial cells, we first demonstrated that IS impaired the valsartan-mediated phosphorylation of eNOSThr495, nitric oxide production and tube formation via NADPH oxidase (NOX) and protein kinase C (PKC) phosphorylation, but this effect was suppressed by cotreatment with apocynin and calphostin C. In vivo, IS attenuated valsartan-induced angiogenesis in Matrigel plugs in mice. Moreover, in subtotal nephrectomy mice who underwent hindlimb ischemic surgery, valsartan significantly increased the mobilization of endothelial progenitor cells in circulation as well as the reperfusion of blood flow and density of CD31+ capillaries in ischemic limbs. However, IS attenuated the protective effect of valsartan-induced neovascularization and increased the expression of p-PKCαSer657 and p-eNOSThr497 in ischemic limbs. Cotreatment of apocynin and calphostin C reversed the IS impaired-neovascularization and decreased the expression of p-PKCαSer657 and p-eNOSThr497 in ischemic limbs. Our study suggests that the NOX/PKC/eNOS signaling pathway plays a pivotal role in the IS-mediated inhibition of valsartan-conferred beneficial effects on endothelial function in vitro and neovascularization in subtotal nephrectomy mice. We proposed a novel causative role for IS in cardiovascular complications in CKD patients. ? 2020
Subjects
Chronic kidney disease; Indoxyl sulfate; Neovascularization; Valsartan
SDGs
Other Subjects
apocynin; calphostin; cyclic AMP dependent protein kinase; endothelial nitric oxide synthase; indican; matrigel; protein kinase C; reduced nicotinamide adenine dinucleotide phosphate oxidase; valsartan; endothelial nitric oxide synthase; indican; nitric oxide; Nos3 protein, mouse; platelet endothelial cell adhesion molecule 1; Prkca protein, mouse; protein kinase C alpha; valsartan; angiogenesis; animal experiment; animal model; animal tissue; aortic endothelium; Article; blood flow; cell function; circulation; drug effect; endothelial progenitor cell; endothelium cell; human; human cell; in vitro study; in vivo study; limb ischemia; male; mouse; neovascularization (pathology); nephrectomy; nonhuman; priority journal; protein expression; protein phosphorylation; signal transduction; adverse event; animal; cell line; disease model; drug effect; hindlimb; ischemia; metabolism; phosphorylation; vascularization; Animals; Cell Line; Disease Models, Animal; Hindlimb; Humans; Indican; Ischemia; Male; Mice; Neovascularization, Physiologic; Nephrectomy; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1; Protein Kinase C-alpha; Signal Transduction; Valsartan
Publisher
Elsevier B.V.
Type
journal article