T. Sitter et al., D-glucose increases the synthesis of tissue-type plasminogen activator (t-PA) in human peritoneal mesothelial cells, THROMB HAEM, 82(3), 1999, pp. 1171-1176
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.