Angiotensin II activates collagen type I gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and TGF-beta

Hypertension is frequently associated with the development of renal vascula r fibrosis. This pathophysiologic process is due to the abnormal formation of extracellular matrix proteins, mainly collagen type I. In previous studi es, it has been observed that the pharmacologic blockade of angiotensin II (Ang II) or endothelin (ET) blunted the development of glomerulo- and nephr oangiosclerosis in nitric oxide-deficient hypertensive animals by inhibitin g 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 th is interaction. Experiments were performed in vivo on transgenic mice harbo ring the luciferase gene under the control of the collagen I-alpha2 chain p romoter (procol alpha2[I]). Bolus intravenous administration of AngII or ET produced a rapid, dose-dependent activation of collagen I gene in aorta an d 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 I 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 e xperiments, TGF-<beta> (also administered intravenously) produced a rapid i ncrease of procol alpha2(I) in aorta and renal cortical slices (twofold inc rease 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 attenua ted the activation of collagen I gene produced by An-II (P < 0.01). These d ata indicate that AngII can activate collagen I gene in aorta and renal cor tex in vivo by a mechanism(s) requiring participation and/or cooperation of ET and TGF-<beta>.