Roles of prostaglandin E receptors in mesangial cells under high-glucose conditions

Background. High glucose reportedly stimulates prostaglandin (PG) E-2 produ ction and DNA synthesis in mesangial cells (MCs). However, the pathophysiol ogical significance of PGE(2) in MCs has remained unclear. Methods. The effects of prostanoids on [H-3]-thymidine uptake and cAMP prod uction in rat MCs cultured with 5.6 mM glucose, 25 mM glucose, or 5.6 mM gl ucose supplemented with 19.4 mM mannitol were examined. The gene expression of PGE(2) receptor (EP) subtypes in MCs was analyzed with Northern blottin g techniques. Results. Northern blotting indicated EP1 and EP4 gene expression in MCs. EP 1 agonists and PGE(2) stimulated [H-3]-thymidine uptake in MCs. EP1 antagon ists dose dependently attenuated high-glucose-induced [H-3]-thymidine uptak e, which suggests EP1 involvement, by an increase in intracellular Ca2+, in DNA synthesis of MCs. On the other hand, forskolin, db-cAMP, and 11-deoxy- PGE(1), an EP4/EP3/EP2 agonist, significantly decreased DNA synthesis in MC s. These inhibitory effects are thought to be mediated via EP4 as a result of an increase in cAMP synthesis. The effects via EP4 seem to be particular ly important because PGE(2)-induced cAMP synthesis was significantly attenu ated in the high-glucose group compared with the mannitol group, in which [ H-3]-thymidine uptake did not increase in spite of augmented PGE(2) product ion. Conclusion. The increase in DNA synthesis in MCs under high-glucose conditi ons can be explained, at least in part, by the high-glucose-induced inhibit ion of cAMP production via EP4, which augments EP1 function in conjunction with the overproduction of PGE(2).