title: 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.
authors.affiliation: Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan.
authors.forename: Szu-Chun
authors.initials: SC
authors.lastname: Hung
authors.affiliation: Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan.
authors.forename: Ko-Lin
authors.initials: KL
authors.lastname: Kuo
authors.affiliation: Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsin-Lei
authors.initials: HL
authors.lastname: Huang
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tung-Hu
authors.initials: TH
authors.lastname: Tsai
authors.affiliation: Cardiovascular Research Center, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, and Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Cardiovascular Research Center, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Jaw-Wen
authors.initials: JW
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Center, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: Cardiovascular Research Center, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: huangbs@vghtpe.gov.tw.
authors.forename: Po-Hsun
authors.initials: PH
authors.lastname: Huang
authors.affiliation: Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: dctarng@vghtpe.gov.tw.
authors.forename: Der-Cherng
authors.initials: DC
authors.lastname: Tarng
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016026:Bone Marrow Transplantation; D002244:Carbon / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006614:Hindlimb; D006801:Humans; D007200:Indican / Q000097:blood*; D018836:Inflammation Mediators / Q000378:metabolism; D007511:Ischemia / Q000097:blood* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009392:Nephrectomy; D010087:Oxides / Q000494:pharmacology; D012039:Regional Blood Flow; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D014511:Uremia / Q000097:blood* / Q000188:drug therapy
chemical_list: D042501:Angiogenic Proteins; D018836:Inflammation Mediators; D010087:Oxides; D002244:Carbon; C040896:AST 120; D007200:Indican
keywords: chronic kidney disease; endothelial progenitor cells; indoxyl sulfate; interleukin-10; neovascularization