title: Uremic conditions drive human monocytes to pro-atherogenic differentiation via an angiotensin-dependent mechanism.
abstract: OBJECTIVE
  Elevated expression levels of monocytic-ACE have been found in haemodialysis patients. They are not only epidemiologically linked with increased mortality and cardiovascular disease, but may also directly participate in the initial steps of atherosclerosis. To further address this question we tested the role of monocytic-ACE in promotion of atherosclerotic events in vitro under conditions mimicking those of chronic renal failure.
  
  
  RESULTS
  Treatment of human primary monocytes or THP-1 cells with uremic serum as well as PMA-induced differentiation led to significantly up-regulated expression of ACE, further increased by additional treatment with LPS. Functionally, these monocytes revealed significantly increased adhesion and transmigration through endothelial monolayers. Overexpression of ACE in transfected monocytes or THP-1 cells led to development of more differentiated, macrophage-like phenotype with up-regulated expression of Arg1, MCSF, MCP-1 and CCR2. Expression of pro-inflammatory cytokines TNFa and IL-6 were also noticeably up-regulated. ACE overexpression resulted in significantly increased adhesion and transmigration properties. Transcriptional screening of ACE-overexpressing monocytes revealed noticeably increased expression of Angiotensin II receptors and adhesion- as well as atherosclerosis-related ICAM-1 and VCAM1. Inhibition of monocyte ACE or AngII-receptor signalling led to decreased adhesion potential of ACE-overexpressing cells.
  
  
  CONCLUSIONS
  Taken together, these data demonstrate that uremia induced expression of monocytic-ACE mediates the development of highly pro-atherogenic cells via an AngII-dependent mechanism.
authors.affiliation: Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, Germany.
authors.forename: Bogusz
authors.initials: B
authors.lastname: Trojanowicz
authors.affiliation: Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Ulrich
authors.affiliation: Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Seibert
authors.affiliation: Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Fiedler
authors.affiliation: Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Girndt
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002216:Captopril / Q000494:pharmacology; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D014511:Uremia / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D008070:Lipopolysaccharides; D000804:Angiotensin II; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D019808:Losartan