Angiotensin II induces fibronectin expression in human peritoneal mesothelial cells via ERK1/2 and p38 MAPK

Abstract

The renin-angiotensin system has been implicated in the pathogenesis of fibrosis in various organs. However, its involvement in peritoneal fibrosis, a crucial complication of peritoneal dialysis, is unclear. Human peritoneal mesothelial cells (HPMC) play a major role in peritoneal fibrosis by producing extracellular matrix (ECM). However, there is scant data regarding the effect of angiotensin II (Ang II) on ECM expression and signal transduction pathways in HPMC. The concentration of Ang II in the peritoneal dialysis effluent was measured by radioimmunoassay. We investigated the expression of Ang II type 1 (AT1) and type 2 (AT2) receptors by HPMC. We also examined the effect of Ang II upon fibronectin production by HPMC, and dissected the receptor and intracellular signaling pathways involved. Ang II levels in the peritoneal dialysis effluent at the onset of peritonitis were 30 times higher than baseline levels. HPMC expression of AT1 and AT2 receptors was confirmed at the mRNA and protein level by reverse transcriptase-polymerase chain reaction (PCR), Western blotting, and immunocytochemistry. Quantitative reverse transcriptase-PCR and Western blotting showed that 10 nmol/L Ang II increased fibronectin mRNA expression followed by secretion of fibronectin protein. This response was completely inhibited by the AT1 receptor antagonist RNH6270, while the AT2 receptor antagonist PD123319 had no effect. Ang II-induced fibronectin expression was mediated by the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK), but not c-Jun N-terminal kinase. These results indicate the potential importance of ERK1/2 and p38 MAPK signaling pathways in Ang II-induced fibronectin expression in HPMC, and suggest the therapeutic potential of AT1 receptor blockers in the prevention or treatment of peritoneal fibrosis in patients on peritoneal dialysis.