ACE inhibitor and AT1-receptor blocker attenuate the production of VEGF in mesothelial cells

Abstract

◆ Objective: Human mesothelial cells (HMC) are a major source of intraperitoneal vascular endothelial growth factor (VEGF) and by that are presumably involved in complications of long-term peritoneal dialysis (PD), such as ultrafiltration failure. This prompted us to look for agents that reduce basic mesothelial VEGF production and abrogate VEGF-overproduction induced by proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1α (IL-1α). Angiotensin-converting enzyme (ACE) inhibition was found to preserve peritoneal function and ameliorate morphologic changes in a rat PD model. The present in vitro study was designed to investigate the effect of the ACE inhibitors captopril and enalapril, and the angiotensin II type 1-receptor (AT1) antagonist losartan on mesothelial VEGF synthesis. ◆ Methods: HMC were isolated from omental tissue and taken into culture. VEGF antigen concentrations were measured in the cell supernatant by ELISA. VEGF mRNA levels were determined by real-time polymerase chain reaction. ◆ Results: Incubation of HMC with captopril (100-1000 μmol/L) resulted in a concentration-dependent attenuation of VEGF synthesis. Incubation with captopril (500-1000 μmol/L), enalapril (100-1000 μmol/L), and losartan (1-100 μmol/L) significantly decreased inflammatory mediator (TNF-α, IL-1α)-induced mesothelial VEGF overproduction. ◆ Conclusion: The results indicate that ACE inhibitors and AT1-receptor blockers are capable of effectively attenuating the overproduction of VEGF due to proinflammatory cytokine stimuli. These data suggest that locally produced angiotensin II in the peritoneal cavity may be a potential therapeutic target in ultrafiltration failure during long-term PD. Copyright © 2007 International Society for Peritoneal Dialysis.