PGE2 upregulates renin through E-prostanoid receptor 1 via PKC/cAMP/CREB pathway in M-1 cells

ALEXIS ANTONIO GONZALEZ PARRA, Nicolas Salinas-Parra, Dan Leach, L. Gabriel Navar, Minolfa C. Prieto

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

During the early phase of ANG II-dependent hypertension, tubular PGE2is 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. PGE2 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 PGE2in 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 10-6 M PGE2maximally 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 PKC_ dominant negative. Both strategies blunted the PGE2-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 PGE2increases 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 PGE2that stimulates renin in the CD, resulting in increased tubular ANG II formation and further stimulation of renin.

Original languageEnglish
Pages (from-to)F1038-F1049
JournalAmerican Journal of Physiology - Renal Physiology
Volume313
Issue number4
DOIs
StatePublished - 9 Oct 2017

Keywords

  • CREB
  • Gene expression
  • Kidney
  • Prostaglandin E
  • Protein kinase C

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