ACE inhibitor and AT1-receptor blocker attenuate the production of VEGF in mesothelial cells.
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-alpha) and interleukin-1alpha (IL-1alpha). 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 micromol/L) resulted in a concentration-dependent attenuation of VEGF synthesis. Incubation with captopril (500-1000 micromol/L), enalapril (100-1000 micromol/L), and losartan (1-100 micromol/L) significantly decreased inflammatory mediator (TNF-alpha, IL-1alpha)-induced mesothelial VEGF overproduction.


CONCLUSIONS
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 longterm PD.
Sauter
Matthias
M
Department of Nephrology, Medizinische Poliklinik - Innenstadt, Germany. Matthias.Sauter@med.uni-muenchen.de
Cohen
Clemens D
CD
Wörnle
Markus
M
Mussack
Thomas
T
Ladurner
Roland
R
Sitter
Thomas
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D018929:Cell Culture Techniques; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators; D009852:Omentum / Q000166:cytology; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D018836:Inflammation Mediators; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A