Indoxyl sulfate suppresses endothelial progenitor cell–mediated neovascularization

Abstract

Patients with chronic kidney disease have an increased prevalence of peripheral arterial disease. Endothelial progenitor cells (EPC) are pivotal in neovascularization, but their role in mediating peripheral arterial disease in chronic kidney disease is not fully known. Here we studied the impact of indoxyl sulfate, a protein-bound uremic toxin, on EPC function in response to tissue ischemia or cell hypoxia in mice that underwent subtotal nephrectomy or sham operation. At 16 weeks, unilateral hindlimb ischemia was induced in all. Four weeks later, subtotal nephrectomy mice had significantly increased plasma levels of indoxyl sulfate, reduced reperfusion, decreased EPC mobilization, and impaired neovascularization in ischemic hindlimbs compared with control mice. Treatment with AST-120, an oral adsorbent of uremic toxins, reversed these changes. Ischemia-induced protein expression including phospho-eNOS, phospho-STAT3, interleukin-10, and VEGF were significantly decreased in ischemic hindlimbs of subtotal nephrectomy mice versus control mice; all effects were reversed by AST-120. Subtotal nephrectomy mice fed a diet with indole for 12 weeks resulted in impaired neovascularization in ischemic hindlimbs; also reversed by AST-120. In cultured human EPCs, VEGF expression was increased in hypoxia through HIF-1α and interleukin-10/STAT3 signaling; effects suppressed by pretreatment with indoxyl sulfate. Moreover, indoxyl sulfate markedly attenuated hypoxia-induced EPC migration and tube formation. Thus, indoxyl sulfate may be a therapeutic target for EPC-rescue of impaired neovascularization in patients with chronic kidney disease and peripheral arterial disease.

Mineral bone disorders in chronic kidney disease

“…VC can be considered as two major types: intimal calcification associated with atherosclerosis, and medial calcification that involves damaged vascular smooth muscle cells (VSMC), leading to increased vascular stiffness and decreased vascular elasticity . The factors involving the pathophysiology of VC in CKD include abnormal serum calcium and phosphate levels, hyperparathyroidism, increased matrix degradation, VSMC apoptosis, decreased glutamate protein in matrix, and systemic inflammation . The factors above‐mentioned activated the osteoblastic transformation of VSMC and the VC.…”

Indoxyl Sulfate: A Novel Cardiovascular Risk Factor in Chronic Kidney Disease

“…Indoxyl sulfate has been shown to have direct effects on EPCs through NO‐dependent mechanisms both in vitro and in vivo . In a recent study, we aimed to elucidate whether indoxyl sulfate could impede neovascularization in ischemic hindlimbs through modulating EPC function in CKD . Subtotal nephrectomy was undertaken in 8‐week‐old male C57BL/6 mice, which were then divided into 3 groups including the vehicle group, the indole group, and the indole plus AST‐120 group.…”

Hypoxia, HIF, and Associated Signaling Networks in Chronic Kidney Disease

“…Among all uncovered angiogenic factors, vascular endothelial growth factor (VEGF) is critical in the maintenance of peritubular capillaries. As the direct target gene of HIF, VEGF is primarily controlled by HIF-1 [118,119]. However, excessive VEGF expression in the tubular cells may be detrimental, because increased tubular VEGF expression may propel fibrosis and cyst formation, and aggravate kidney injury [120,121].…”