Angiotensin II modulates cell growth-related events and synthesis of matrix proteins in renal interstitial fibroblasts

Abstract

The renin-angiotensin system seems to play an important role in the pathogenesis of renal interstitial fibrosis. However, the potential direct effects of angiotensin II (Ang II) on cultured renal fibroblasts have been little studied. We have observed that rat renal interstitial fibroblasts (NRK 49F cell line) possess AT1 receptors coupled to intracellular calcium mobilization. Exposure of these cells to Ang II induced several short and long growth-related metabolic events mediated by the AT1 receptor, including c-fos gene expression, changes in cell cycle and cell proliferation. Activation of interstitial fibroblasts by Ang II could also contribute to extracellular matrix accumulation. Stimulation with Ang II increased mRNA expression of TGF-beta 1, fibronectin and type I collagen. In fact, Ang II enhanced fibronectin production via AT1 receptors by a process depending on autocrine TGF-beta secretion. The mechanism of some Ang II actions (calcium mobilization and fibronectin production) depended on protein kinase C and tyrosine kinase activation. We further investigated whether renal fibroblasts could express some components of the renin-angiotensin system. These cells constitutively expressed the angiotensinogen gene that was up-regulated by Ang II. Collectively, these results indicate that in renal interstitial fibroblasts Ang II causes hyperplasia and extracellular matrix production via the AT1 receptor. Ang II may initiate a positive feedback regulation of fibroblasts growth, inducing the expression of TGF-beta 1 and angiotensinogen genes. Ang II, acting directly on interstitial fibroblasts, may be implicated in the pathogenesis of renal fibrosis.