HIGH GLUCOSE INCREASES PROSTAGLANDIN E-2 SYNTHESIS IN HUMAN PERITONEAL MESOTHELIAL CELLS - ROLE OF HYPEROSMOLARITY

Peritoneal mesothelial cells are considered the pre-dominant source of peritoneal prostanoid formation because: they represent the largest r esident cell population in the peritoneal cavity. The present study wa s designed to evaluate the effect of D-glucose, which is widely used i n commercially available peritoneal dialysis fluids as an osmotic comp ound, on the synthesis of prostaglandins in cultured human mesothelial cells (HMC). Analysis of eicosanoid synthesis in HMC by reversed-phas e HPLC revealed that 6-keto-PGF(1 alpha), the spontaneous hydrolysis p roduct of prostacyclin (PGI(2)), and prostaglandin E-2 (PGE(2)) were t he main eicosanoids produced. Addition of D-glucose resulted in a time - and concentration-dependent (30 to 120 mM) increase in PGE(2) produc tion in HMC (24 h, 90 mM: 3.9 +/- 0.5 ng/10(5) cells versus 2.3 +/- 0. 3 in untreated cells; P < 0.05). Mannitol (90 mM) or L-glucose (90 mM) , nonmetabolizable osmotic compounds, also led to a significant (P < 0 .05) but less intense increase in PGE(2) synthesis (3.3 +/- 0.4 and 3. 2 +/- 0.5 ng/10(5) cells, respectively). Increased PGE(2) synthesis wa s completely blunted by coincubation With the specific protein kinase C (PKC) inhibitor Ro 31-8220 or downregulation of PKC activity by prei ncubation with phorbol myristate acetate for 16 h. Furthermore, coincu bation with PD 98059, an inhibitor of the mitogen-activated protein ki nase/extracellular signal-regulated kinase pathway, also inhibited inc reased PGE(2) synthesis by D-glucose or mannitol. In contrast, the iso -osmolar glucose polymer icodextrin, which is used as an alternative t o D-glucose in peritoneal dialysis solutions, had no effect on PGE(2) synthesis. These data indicate that D-glucose and metabolically inert sugars increase PGE(2) synthesis in NMC at least in part by hyperosmol arity and that this effect requires activation of PKC and the mitogen- activated protein kinase/extracellular signal-regulated kinase pathway of intracellular signaling.