Indoxyl sulfate-induced activation of (pro)renin receptor promotes cell proliferation and tissue factor expression in vascular smooth muscle cells

• Published in: PloS one Vol. 9; no. 10; p. e109268
• Main Authors: Yisireyili, Maimaiti, Saito, Shinichi, Abudureyimu, Shaniya, Adelibieke, Yelixiati, Ng, Hwee-Yeong, Nishijima, Fuyuhiko, Takeshita, Kyosuke, Murohara, Toyoaki, Niwa, Toshimitsu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.10.2014; Public Library of Science (PLoS)
• Subjects: Acetylcysteine; Activation; Adenine; Animals; Antioxidants; Antioxidants (Nutrients); Aorta; Aorta - metabolism; Aorta - pathology; Aromatic compounds; Autophagy; Biochemistry; Biology and Life Sciences; Cardiology; Cardiovascular diseases; Cell activation; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - genetics; Chronic kidney failure; Circulatory system; Comparative analysis; Gene Expression Regulation - drug effects; Health risks; Humans; Hydrocarbons; Hypertension; Immunoglobulins; Immunohistochemistry; Indican - administration & dosage; Inhibition; Kidney diseases; Kidneys; Kinases; Medicine; Medicine and Health Sciences; Mortality; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscles; Myocytes, Smooth Muscle - metabolism; NAD(P)H oxidase; NADPH-diaphorase; NF-κB protein; Niacinamide; Nicotinamide; Nicotinamide adenine dinucleotide; Onium Compounds - administration & dosage; Organic Anion Transporters, Sodium-Independent - biosynthesis; Organic Anion Transporters, Sodium-Independent - genetics; Oxidases; Oxygen; Phosphates; Proteins; Rats; Reactive oxygen species; Receptors, Cell Surface - biosynthesis; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Renin; RNA, Small Interfering - genetics; Rodents; Senescence; Smooth muscle; Sulfate; Sulfates; Thromboplastin - biosynthesis; Thrombosis; Tissue factor; Transporter; University graduates; Vacuolar Proton-Translocating ATPases - biosynthesis; La Jolla California; United States > US; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0109268

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. 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.