Angiotensin II activates collagen I gene through a mechanism involving theMAP/ER kinase pathway

Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood press ure. In previous studies we have found that angiotensin II (Ang II) partici pates in the hypertension-associated aortic and renal vascular fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II recept or to collagen I gene activation. To this end, we used a novel strain of tr ansgenic mice harboring the luciferase gene under the control of the collag en I-alpha(2) chain promoter [procol alpha(2)(I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procol alpha(2)(I) activity in freshl y isolated aortas and renal cortical slices (P<0.01) followed by similar in crease in procol alpha(2)(I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK /ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway ( SB202190) and blockade of the release of the transcription factor NF kappa B (PDTC) did not have any effect in the Ang II-induced activation of the co llagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c-fos proto-oncogene. This increase of c-Sos mRNA expression was bl ocked by PD98059; in addition, curcumin, a blocker of the transcriptional f actor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-beta (TGF-beta ), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-beta-induced activation of proco l alpha(2)(I). These data indicate that the cellular events after AT1 recep tor stimulation and leading to activation of collagen I gene expression req uire activation of both the MAPK/ERK and TGF-beta signaling pathways.