Therapeutic approach towards salt-sensitive hypertension via activation of prostaglandin E2-EP4 receptors

点击翻译按钮获取中文摘要

Cyclooxygenase-1 (COX-1) deficient mice are salt sensitive and polyuric under high salt diet. We have focused on the prostaglandin E2-EP4 receptor signaling pathway as a cause of these phenotypes. EP4 has been shown to enhance water absorption via cAMP production and, as anticipated, the administration of EP4 agonist : ONO-AE1-329 (EP4AG, 6x10^<-10>mol/gram body weight every one hour) in rats increased water absorption. On the other hand, sodium absorption was not enhanced by EP4AG. EP4AG (10^<-6>M) in cultured mice collecting duct (M-1) cells reduced the abundance of the phosphorylated Akt, Sgk1 and p38 proteins and increased the expression of MAP kinase phosphatase 1 (MKP1) mRNA. P38 inhibitor (BIRB796 : 10^<-5>M) reduced the protein abundance of phosphorylated Akt and Sgk-1, which could be a counteracting mechanism to cAMP-mediated sodium absorption. In conclusion, EP4AG can be an effective agent as a mediator for therenal tubular water and electrolyte transports.