Sauter Matthias, Cohen Clemens D, Wörnle Markus, Mussack Thomas, Ladurner Roland, Sitter Thomas
Department of Nephrology, Medizinische Poliklinik - Innenstadt, Germany.
Perit Dial Int. 2007 Mar-Apr;27(2):167-72.
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.
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.
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.
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.
人腹膜间皮细胞（HMC）是腹膜内血管内皮生长因子（VEGF）的主要来源，据此推测其与长期腹膜透析（PD）的并发症有关，如超滤失败。这促使我们寻找能够减少间皮细胞基础VEGF产生，并消除由促炎细胞因子如肿瘤坏死因子α（TNF-α）和白细胞介素-1α（IL-1α）诱导的VEGF过度产生的药物。已发现血管紧张素转换酶（ACE）抑制可维持大鼠PD模型的腹膜功能并改善形态学变化。本体外研究旨在探讨ACE抑制剂卡托普利和依那普利以及血管紧张素II 1型受体（AT1）拮抗剂氯沙坦对间皮细胞VEGF合成的影响。
从网膜组织中分离出HMC并进行培养。通过ELISA测量细胞上清液中的VEGF抗原浓度。通过实时聚合酶链反应测定VEGF mRNA水平。
用卡托普利（100 - 1000 μmol/L）孵育HMC导致VEGF合成呈浓度依赖性减弱。用卡托普利（500 - 1000 μmol/L）、依那普利（100 - 1000 μmol/L）和氯沙坦（1 - 100 μmol/L）孵育可显著降低炎症介质（TNF-α，IL-1α）诱导的间皮细胞VEGF过度产生。
结果表明，ACE抑制剂和AT1受体阻滞剂能够有效减弱促炎细胞因子刺激导致的VEGF过度产生。这些数据表明，腹膜腔内局部产生的血管紧张素II可能是长期PD超滤失败的潜在治疗靶点。
