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.