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 μM), p42/p44
MAPK (PD98059, 50 μM) 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.(Korean J Med 71:518-526, 2006)
Key Words : Peritoneal dialysis, Insulin, VEGF |
PDF Links
Full text via DOI
Download Citation
