Investigation of effects of angiotensin type 2 receptors on extracellular matrix synthesis for renal therapy

点击翻译按钮获取中文摘要

In this study, we examined the effects of angiotensin II type 1 (ATI) and type 2 (AT2) receptor stimulation on synthesis of extracellular matrix proteins, including collagen and proteoglycans using a vascular smooth muscle cell line (VSMG-AT2) expressing AT2 receptors. Stimulation of these cells with the AT2 receptor agonist CGP42112A did not cause a significant change in ERK1/2 activity but caused a small but significant decrease in protein tyrosine phosphatase activity. The stimulation of the AT2 receptor also caused a dose- and time-dependent increase in both cell-associated and secreted collagen synthesis to 148+17% of control levels (p<0.05), The effects of AT1 and AT2 receptor stimulation on proteoglycan synthesis were next examined. Stimulation of the AT1 receptor caused a dose- and time-dependent increase in proteoglycan synthesis. DEAE-Sephacel chromatography revealed an increase in both HSPG and CS/DSPG, while Northern blot analysis showed' that biglycan, versican, and perlecan mRNA were increased, Stimulation of the AT2 receptor alone also caused a small but significant increase in proteoglycan synthesis which was unaffected by tyrosine kinase and MEK inhibitors but attenuated by pertussis toxin. In vivo studies using angiotensin receptor blocker (ARB) showed that ARB treatment caused a decrase in biglycan and decorin mRNA but an increase in versican mRNA. These results suggested that angiotensin II can regulate extracellular matrix synthesis by both AT1 and AT2 receptors through multiple mechanisms.