gms | German Medical Science

Angiotensin II (Ang II) is known to be involved in tissue fibrosis, repair and remodelling through the induction of extracellular matrix (ECM) protein synthesis. Recently, we demonstrated the expression of a complete renin-angiotensin-system in human skin. Based on the findings in fibroblasts of non-cutaneous origin, we speculated, that Ang II may be involved in ECM generation in human dermal primary fibroblasts.

Stimulation of these cells with 10-7 M Ang II caused a fourfold increase in collagen I synthesis. This effect could be blocked by PD 98048, an inhibitor of ERK 1/2 activation, and also by AG 1478, an inhibitor of EGF-receptor transactivation. Furthermore, we could show by Western Blot analysis that Ang II leads to ERK 1/2 activation with a maximum after 5 min, and to EGF-receptor transactivation with a maximum after 3 min. C-fos expression represents another step in Ang II coupled signalling leading to ECM synthesis. Incubation with Ang II led to a marked increase in c-fos mRNA reaching a maximal effect after 30 minutes as detected by semi-quantitative RT-PCR. This increase could be reduced by approx. 50 % by co-incubation with both, the specific AT1-receptor antagonist Irbesartan (10-6 M) or the specific AT2-receptor antagonist PD 123319 (10-6 M). Co-incubation with both receptor antagonists completely abolished Ang II induced c-fos expression. An approx. 50% inhibition of Ang II induced c-fos expression was also achieved by co-incubation with AG 1478 or PD 98048, respectively. The inhibitory effects of AG 1478 and PD 98048 were dose-dependent, but even higher concentrations of these agents were not able to block Ang II induced c-fos expression completely. We conclude, that Ang II stimulates collagen I synthesis in human skin, and that this effect is mediated by EGF-receptor transactivation, ERK 1/2 activation, and most likely c-fos expression. Ang II induced c-fos expression seems to participate in further, so far unknown AT2-receptor mediated actions.