title: Indoxyl sulfate-induced activation of (pro)renin receptor promotes cell proliferation and tissue factor expression in vascular smooth muscle cells.
abstract: Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease (CVD). (Pro)renin receptor (PRR) is activated in the kidney of CKD. The present study aimed to determine the role of indoxyl sulfate (IS), a uremic toxin, in PRR activation in rat aorta and human aortic smooth muscle cells (HASMCs). We examined the expression of PRR and renin/prorenin in rat aorta using immunohistochemistry. Both CKD rats and IS-administrated rats showed elevated expression of PRR and renin/prorenin in aorta compared with normal rats. IS upregulated the expression of PRR and prorenin in HASMCs. N-acetylcysteine, an antioxidant, and diphenyleneiodonium, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase, suppressed IS-induced expression of PRR and prorenin in HASMCs. Knock down of organic anion transporter 3 (OAT3), aryl hydrocarbon receptor (AhR) and nuclear factor-κB p65 (NF-κB p65) with small interfering RNAs inhibited IS-induced expression of PRR and prorenin in HASMCs. Knock down of PRR inhibited cell proliferation and tissue factor expression induced by not only prorenin but also IS in HASMCs.
  
  
  CONCLUSIONS
  IS stimulates aortic expression of PRR and renin/prorenin through OAT3-mediated uptake, production of reactive oxygen species, and activation of AhR and NF-κB p65 in vascular smooth muscle cells. IS-induced activation of PRR promotes cell proliferation and tissue factor expression in vascular smooth muscle cells.
authors.affiliation: Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Maimaiti
authors.initials: M
authors.lastname: Yisireyili
authors.affiliation: Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shaniya
authors.initials: S
authors.lastname: Abudureyimu
authors.affiliation: Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yelixiati
authors.initials: Y
authors.lastname: Adelibieke
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hwee-Yeong
authors.initials: HY
authors.lastname: Ng
authors.affiliation: Biomedical Research Laboratories, Kureha Co., Tokyo, Japan.
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Nishijima
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takeshita
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan; Faculty of Health and Nutrition, Shubun University, Aichi, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Niwa
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007200:Indican / Q000008:administration & dosage; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009861:Onium Compounds / Q000008:administration & dosage; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D013925:Thromboplastin / Q000096:biosynthesis*; D025262:Vacuolar Proton-Translocating ATPases / Q000096:biosynthesis*; D000093342:Prorenin Receptor
chemical_list: D007200:Indican; D009861:Onium Compounds; D029362:Organic Anion Transporters, Sodium-Independent; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D013925:Thromboplastin; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor; C114338:organic anion transport protein 3; C007517:diphenyleneiodonium