title: The mechanism of long-term low-dose asymmetric dimethylarginine inducing             transforming growth factor-β expression in endothelial cells.
abstract: Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase             (NOS) inhibitor, accumulates in plasma during chronic kidney disease (CKD). High             plasma levels of ADMA can increase transforming growth factor-β (TGF-β) expression,             related to renal fibrosis, but the precise molecular mechanism is not explicit.             The present study was designed to determine the mechanism through which long-term             low-dose ADMA induces TGF-β expression in endothelial cells and to investigate             the molecular mechanism of its action. Human umbilical vein endothelial cells             (HUVECs) were exposed to low-dose ADMA (5 and 10 µmol/l) for 7 passages and TGF-β             expression was determined. Human renal glomerular endothelial cells (HRGECs) were             exposed to high-dose ADMA (100 µmol/l) which were used to clarify the molecular             mechanism. The results showed that long-term low-dose ADMA (5 and 10 µmol/l) increases             TGF-β production in both mRNA and protein levels in HUVECs in a time-dependent             manner. We confirmed that exogenous ADMA (100 µmol/l) significantly enhanced stress             fiber formation in HRGECs and upregulated TGF-β expression. Such effects of ADMA             in HRGECs were inhibited by pre-treatment with actin depolymerizing agent, actin             stabilizing agent, p38 MAPK inhibitor and NADPH oxidase inhibitor. In addition,             we demonstrated that ADMA (100 µmol/l) significantly activated nuclear factor-κB             (NF-κB) in HRGECs, which was markedly attenuated by actin depolymerizing agent,             actin stabilizing agent, p38 MAPK inhibitor and NADPH oxidase inhibitor. In brief,             the present study demonstrated that long-term low-dose ADMA induces TGF-β expression             in endothelial cells at both the gene and protein levels. The actin cytoskeleton             may be involved in modulation of ADMA-induced NF-κB activation and the ensuing             TGF-β expression in HRGECs.
authors.affiliation: Department of Nephrology, Affiliated Beijing Friendship Hospital, Faculty of Kidney Diseases, Capital Medical University, Xi Cheng, Beijing 100050, PR China.
authors.forename: Yiduo
authors.initials: Y
authors.lastname: Feng
authors.forename: Dongliang
authors.initials: D
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qidong
authors.initials: Q
authors.lastname: Zhang
authors.forename: Wenhu
authors.initials: W
authors.lastname: Liu
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000199:Actins; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C487735:dimethylarginine; D001120:Arginine; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases