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-β (TGF-β) could be a player in this interaction. Experiments were performedin vivoon transgenic mice harboring the luciferase gene under the control of the collagen I-α2 chain promoter (procolα2[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 procolα2(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-β (also administered intravenously) produced a rapid increase of procolα2(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-β). 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 cortexin vivoby a mechanism(s) requiring participation and/or cooperation of ET and TGF-β.
The importance of thrombus organization and stellate cell phenotype in collagen I gene expression in human, coronary atherosclerotic and restenotic lesions