PAR-1 mediates the thrombin-induced mesothelial cell overproduction of VEGF and PAI-1.

Thrombin mediates an excess in the production of neoangiogenetic (VEGF) and profibrotic (PAI-1) factors in human peritoneal mesothelial cells (HMC). The mechanisms leading to this overproduction have not been elucidated so far; in the context of peritoneal dialysis it can result in impaired peritoneal membrane function. This study was performed to evaluate the presence of the thrombin receptor protease-activated receptor-1 (PAR-1) in HMC and to characterize its function in the thrombin-dependent effects mentioned above. All experiments were performed using cultured primary HMC. Real-Time PCR and Western Blot were used to evaluate PAR-1; ELISA and Real-Time PCR were employed to examine PAR-1 effects on target mediators. We found that cultivated primary HMC show a basal presence of PAR-1. Stimulation with IL-1β induced an increase of the mesothelial PAR-1 expression whereas stimulation with glycosilated human serum albumin or the ligand thrombin itself resulted in decreased PAR-1 expression. Stimulation with the specific PAR-1 ligand TFLLR-NH(2) caused increased VEGF and PAI-1 levels similar to stimulation with thrombin, whereas preincubation with PAR-1 blocking antibodies ATAP2 and WEDE15 attenuated the thrombin-induced overproduction of VEGF and PAI-1. HMC express PAR-1 and the receptor is involved in thrombin effects on these cells. These findings may be a basis for pharmacological prevention of neoangiogenesis and adhesions in the context of peritoneal dialysis and peritonitis.

Citation

Franziska Belling, Andrea Ribeiro, Markus Wörnle, Roland Ladurner, Thomas Mussack, Thomas Sitter, Matthias Sauter. PAR-1 mediates the thrombin-induced mesothelial cell overproduction of VEGF and PAI-1. The International journal of artificial organs. 2013 Feb;36(2):97-104

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PMID: 23280079

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