D-glucose increases the synthesis of tissue-type plasminogen activator (t-PA) in human peritoneal mesothelial cells

Physical and chemical irritation of the peritoneum through glucose-based hy perosmolar dialysis solutions results in a nonbacterial serositis with fibr inous exudation. Thereby, human peritoneal mesothelial cells (HMC) play an important role in maintaining the balance between the peritoneal generation and degradation of fibrin by expressing the fibrinolytic enzyme tissue-typ e plasminogen activator (t-PA) as well as the specific plasminogen activato r inhibitor-1 (PAI-1). In this study, we analyzed the effect of D-glucose a nd metabolically inert monosaccharides on the synthesis of t-PA and PAI-1 i n cultured HMC. Incubation of HMC with D-glucose or the metabolically inert monosaccharides mannitol and L-glucose (5-90 mM) resulted in a time- and concentration-dep endent increase in t-PA mRNA expression and antigen secretion without affec ting PAI-1 synthesis. A similar effect was evident when HMC were first expo sed sequentially to pooled spent peritoneal dialysis effluent for up to 4 h ours, and subsequently incubated for 20 hours in control medium. The stimul ating effect of high D-glucose on t-PA expression in HMC was prevented by t reating the cells with different protein kinase C (PKC) inhibitors (Ro 31-8 220, Go 6976), but could not be mimicked by the PKC-activating phorbol eate r PMA, indicating that this effect of high glucose is dependent on PKC acti vity, but not mediated through PKC activation. Also, using specific inhibit ors (PD 98059, SE 203580) and activators (PMA, anisomycin, IL-1 alpha of th e major routes of the mitogen-activated protein kinases (MAPKs) cascade, we found no evidence for a role of this cascade in regulating t-PA expression in HMC. We conclude that hyperosmolarity induces t-PA (but not PAI-1) in HMC via a regulatory mechanism that requires active PKC, but that does not involve a major pathway in the MAPK cascade.