PGE₂upregulates renin through E-prostanoid receptor 1 via PKC/cAMP/CREB pathway in M-1 cells

Abstract

During the early phase of ANG II-dependent hypertension, tubular PGE is increased. Renin synthesis and secretion in the collecting duct (CD) are upregulated by ANG II, contributing to further intratubular ANG II formation. However, what happens first and whether the triggering mechanism is independent of tubular ANG II remain unknown. PGE stimulates renin synthesis in juxtaglomerular cells via E-prostanoid (EP) receptors through the cAMP/cAMP-responsive element-binding (CREB) pathway. EP receptors are also expressed in the CD. Here, we tested the hypothesis that renin is upregulated by PGE in CD cells. The M-1 CD cell line expressed EP1, EP3, and EP4 but not EP2. Dose-response experiments, in the presence of ANG II type 1 receptor blockade with candesartan, demonstrated that 10 M PGE maximally increases renin mRNA (approximately 4-fold) and prorenin/renin protein levels (approximately 2-fold). This response was prevented by micromolar doses of SC-19220 (EP1 antagonist), attenuated by the EP4 antagonist, L-161982, and exacerbated by the highly selective EP3 antagonist, L-798106 (~10-fold increase). To evaluate further the signaling pathway involved, we used the PKC inhibitor calphostin C and transfections with PKCα dominant negative. Both strategies blunted the PGE-induced increases in cAMP levels, CREB phosphorylation, and augmentation of renin. Knockdown of the EP1 receptor and CREB also prevented renin upregulation. These results indicate that PGE increases CD renin expression through the EP1 receptor via the PKC/cAMP/CREB pathway. Therefore, we conclude that during the early stages of ANG II-dependent hypertension, there is augmentation of PGE that stimulates renin in the CD, resulting in increased tubular ANG II formation and further stimulation of renin.

Prostaglandin E2 confers protection against diabetic coronary atherosclerosis by stimulating M2 macrophage polarization via the activation of the CREB/BDNF/TrkB signaling pathway

“…Another key finding of the current study was that PGE2 activated the CREB/BDNF/TrkB signaling pathway, which induced KLF4 expression and then stimulated the polarization of macrophage M2 in DMAS mice. In a prior study, PGE2 was found to increase the level of cAMP and the extent of CREB phosphorylation 29 . Similarly, another study also confirms that BDNF expression and the extent of CREB phosphorylation are increased by treatment with the PGE2 analog, 16,16 dimethyl PGE2 (dmPGE2), in dorsal root ganglion explant cultures 30 .…”

Connexin Hemichannels Contribute to the Activation of cAMP Signaling Pathway and Renin Production

“…cAMP is the major second messenger involved in the control of renin production [ 9 , 11 , 38 ]. In this study, we observed that the activation of the cAMP pathway in As4.1 cells with adenyl cyclase activator forskolin resulted in a time-dependent elevation in renin protein level at the MW of 50 kDa ( Figure 4 A).…”

“…The accumulated cAMP activates PKA, which phosphorylates several proteins and regulates a wide spectrum of cell behaviors. It has been reported that elevated cAMP stimulates renin gene expression in JG cells by phosphorylation of CREB through PKA [ 9 , 11 ]. Consistent with these reports, the elevation in renin in this study was preceded by CREB phosphorylation.…”

“…Oppositely, elevation in intracellular Ca 2+ suppresses adenylyl cyclase and inhibits renin [ 5 ]. In fact, cAMP is a well-characterized secondary messenger in stimulation of renin synthesis and secretion [ 8 , 9 , 10 , 11 ]. cAMP-elevating chemicals such as prostaglandins, kinins, and alpha-adrenergic agonists, all stimulate renin, whereas agents that inhibit the cAMP pathway suppress renin [ 11 , 12 , 13 ].…”

Low Nitric Oxide Bioavailability Increases Renin Production in the Collecting Duct

“…Although, cAMP/PKA is the main signaling pathway involved in CREB phosphorylation, PKC can also phosphorylate CREB (Brindle and Montminy, 1992). However, we demonstrated that in the CD, the PKC pathway plays a major effect on the activation of renin synthesis (Gonzalez et al, 2015(Gonzalez et al, , 2017Lara et al, 2017).…”