Effect of insulin on VEGF synthesis of peritoneal mesothelial cells: possible implications of intraperitoneal insulin on the long-term peritoneal function

Kang, Duk Hee

Abstract

BACKGROUND: Intraperitoneal (IP) insulin administration in peritoneal dialysis (PD) patients has several advantages, including the prevention of major fluctuations of blood glucose and hyperinsulinemia and the formation of insulin antibodies. However, the effects of IP insulin on dialysis efficacy, ultrafiltration and the ultimate peritoneal function have not been investigated. Ultrafiltration failure is the most important functional abnormality during PD, which is now known to be associated with increased peritoneal vascular remodeling and vascular endothelial growth factor (VEGF) synthesis. There are also some evidences of insulin-induced vascular remodeling in other organs. Therefore, we investigated whether insulin regulates VEGF synthesis in human peritoneal mesothelial cells (HPMC), and also compared its signaling pathway to the glucose-induced signaling for VEGF synthesis.
METHODS
The expression of VEGF mRNA and protein was evaluated in HPMC stimulated with insulin (0.1-100 mM) and high glucose (30 mM); the evaluation was done by RT-PCR and ELISA with an examination of related signal transduction system, including p38, p42/44 MAPkinase, protein kinase C (PKC) and PI3 kinase (PI3K).
RESULTS
Insulin (10 nM) increased VEGF mRNA and protein synthesis of the HPMCs from 3 and 24 hours, respectively. Pretreatment with inhibitors of p38 MAPK (SB203580, 10 micrometer), p42/p44 MAPK (PD98059, 50 micrometer) or PI3K (wortmannin, 50 nM) suppressed the insulin-induced VEGF synthesis, whereas there was no effect with PKC inhibition. High glucose (D-glucose, 30 mM)-induced increase in VEGF synthesis was inhibited by pretreatment with inhibitors of p38, p42/p44 MAPK or PKC.
CONCLUSIONS
Insulin per se can induce VEGF synthesis from HPMC via differential mechanisms and signaling pathways from high glucose, which may be related to the later development of peritoneal angiogenesis and ultrafiltration failure. The long-term effects of IP insulin on peritoneal function need to be evaluated in relevant animal models and human subjects.