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

Background. High glucose reportedly stimulates prostaglandin (PG) E-2 production and DNA synthesis in mesangial cells (MCs). However, the pathophysiological significance of PGE(2) in MCs has remained unclear. Methods. The effects of prostanoids on [H-3]-thymidine uptake and cAMP production in rat MCs cultured with 5.6 mM glucose, 25 mM glucose, or 5.6 mM glucose supplemented with 19.4 mM mannitol were examined. The gene expression of PGE(2) receptor (EP) subtypes in MCs was analyzed with Northern blotting techniques. Results. Northern blotting indicated EP1 and EP4 gene expression in MCs. EP1 agonists and PGE(2) stimulated [H-3]-thymidine uptake in MCs. EP1 antagonists dose dependently attenuated high-glucose-induced [H-3]-thymidine uptake, 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 MCs. 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 particularly important because PGE(2)-induced cAMP synthesis was significantly attenuated 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) production. Conclusion. The increase in DNA synthesis in MCs under high-glucose conditions can be explained, at least in part, by the high-glucose-induced inhibition of cAMP production via EP4, which augments EP1 function in conjunction with the overproduction of PGE(2).