title: Angiotensin II activates collagen type I gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and TGF-beta.
abstract: Hypertension is frequently associated with the development of renal vascular fibrosis. This pathophysiologic process is due to the abnormal formation of extracellular matrix proteins, mainly collagen type I. In previous studies, it has been observed that the pharmacologic blockade of angiotensin II (Ang II) or endothelin (ET) blunted the development of glomerulo- and nephroangiosclerosis in nitric oxide-deficient hypertensive animals by inhibiting collagen I gene activation. The purpose of this study was to investigate whether and how AngII interacts with ET to activate the collagen I gene and whether transforming growth factor-beta (TGF-beta) could be a player in this interaction. Experiments were performed in vivo on transgenic mice harboring the luciferase gene under the control of the collagen I-alpha 2 chain promoter (procol alpha 2[I]). Bolus intravenous administration of AngII or ET produced a rapid, dose-dependent activation of collagen I gene in aorta and renal cortical slices (threefold increase over control at 2 h, P < 0.01). The AngII-induced effect on procol alpha 2(I) was completely inhibited by candesartan (AngII type 1 receptor antagonist) and substantially blunted by bosentan (dual ET receptor antagonist) (P < 0.01), whereas the ET-induced activation of collagen I gene was blocked only by bosentan. In subsequent experiments, TGF-beta (also administered intravenously) produced a rapid increase of procol alpha 2(I) in aorta and renal cortical slices (twofold increase over control at 1 h, P < 0.01) that was completely blocked by decorin (scavenger of the active form of TGF-beta). In addition, decorin attenuated the activation of collagen I gene produced by AngII (P < 0.01). These data indicate that AngII can activate collagen I gene in aorta and renal cortex in vivo by a mechanism(s) requiring participation and/or cooperation of ET and TGF-beta.
authors.affiliation: *INSERM U.489, Hôpital Tenon, Paris, France; and AP-HP, Laboratoire de Physiologie, Faculté de Médecine St Antoine, Paris, France.
authors.forename: Fadi
authors.initials: F
authors.lastname: Fakhouri
authors.affiliation: *INSERM U.489, Hôpital Tenon, Paris, France; and AP-HP, Laboratoire de Physiologie, Faculté de Médecine St Antoine, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Placier
authors.affiliation: *INSERM U.489, Hôpital Tenon, Paris, France; and AP-HP, Laboratoire de Physiologie, Faculté de Médecine St Antoine, Paris, France.
authors.forename: Raymond
authors.initials: R
authors.lastname: Ardaillou
authors.affiliation: *INSERM U.489, Hôpital Tenon, Paris, France; and AP-HP, Laboratoire de Physiologie, Faculté de Médecine St Antoine, Paris, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dussaule
authors.affiliation: *INSERM U.489, Hôpital Tenon, Paris, France; and AP-HP, Laboratoire de Physiologie, Faculté de Médecine St Antoine, Paris, France.
authors.forename: Christos
authors.initials: C
authors.lastname: Chatziantoniou
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics*; D004357:Drug Synergism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007672:Kidney Cortex / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D024042:Collagen Type I; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016212:Transforming Growth Factor beta; D000804:Angiotensin II