Prostaglandin E2 Induces Prorenin-Dependent Activation of (Pro)renin Receptor and Upregulation of Cyclooxygenase-2 in Collecting Duct Cells

Abstract

Background Prostaglandin E2 (PGE2) regulates renin expression in renal juxtaglomerular cells. PGE2 acts through E-prostanoid (EP) receptors in the renal collecting duct (CD) to regulate sodium and water balance. CD cells express EP1 and EP4, which are linked to protein kinase C (PKC) and protein kinase A (PKA) downstream pathways, respectively. Previous studies showed that the presence of renin in the CD, and that PKC, and PKA pathways activate its expression. The (pro)renin receptor (PRR) is also expressed in CD cells and its activation enhances cyclooxygenase-2 (COX-2) through extracellular signal–regulated kinase (ERK). We hypothesized that PGE2 stimulates prorenin and renin synthesis leading to subsequent activation of PRR and upregulation of COX-2. Methods We used a mouse M-1 CD cell line that expresses EP1, EP3, and EP4 but not EP2. Results PGE2 (10−6 M) treatment increased prorenin and renin protein levels at 4 and 8 h. No differences were found at 12 h post PGE2 treatment. Phospho-ERK was significantly augmented after 12 h. COX-2 expression was decreased after 4 h of PGE2 treatment, but increased after 12 h. Interestingly, the full-length form of the PRR was upregulated only at 12 h. PGE2 mediated phospho-ERK and COX-2 upregulation was suppressed by PRR silencing. Conclusions Our results suggest that PGE2 induces biphasic regulation of COX-2 through renin-dependent PRR activation via EP1 and EP4 receptors. PRR-mediated increases in COX-2 expression may enhance PGE2 synthesis in CD cells serving as a buffer mechanism in conditions of activated renin angiotensin system.

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

“…Positive feedback regulation. PGE2 signaling through EP2 can in turn boost expression of cOX-2 in polyp tissues (35), and it has been suggested that EP2 may regulate phosphorylated (p)-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), p-protein kinase B (Akt) and p-glycogen synthase kinase 3β (GSK-3β) expression, and increase nuclear translocation of β-catenin in LoVo cancer cells (36). The levels of the cofactors lymphoid enhancer-binding factor-1 (LEF-1) and transcription factor 4 (TcF-4) have also been reported to be upregulated by EP2 in the nucleus, resulting in upregulation of cOX-2 expression (37).…”

(Pro)renin Receptor-Dependent Induction of Profibrotic Factors Is Mediated by COX-2/EP4/NOX-4/Smad Pathway in Collecting Duct Cells

“…Furthermore, we have recently published evidence of the participation of PGE 2 , synthesized by COX-2, in the regulation of prorenin. Prorenin causes further increases in COX-2 expression, generating transient COX-2-prorenin positive feedback (Salinas-Parra et al, 2017). As mentioned before, the relationship between COX-2 and NOX-4 observed in hepatocytes (Sancho et al, 2011) suggests that a similar system regulated by positive feedback may be present in CD cells ( Figure 8 ).…”

The interaction partners of (pro)renin receptor in the distal nephron

“…40,52 Similarly, multiple studies have suggested the influence of COX-2/PGE 2 on PRR-regulated intrarenal RAS in the renal medulla. 17,18,53,54 COX-2 inhibition by NS-398 attenuated Ang II-upregulated PRR protein expression as well as renin activity in primary cultured rat IMCD cells, and almost fully blocked the enhancement of renal medullary PRR protein expression, as well as renal medullary and urinary renin levels in Ang II-infused rats, accompanied with lower blood pressure. 17 These results suggest that the activation of COX-2 contributes to Ang II-stimulated renal medullary PRR expression, thereby leading to the activation of intrarenal RAS during Ang II-induced hypertension.…”

“…22 A similar effect was observed in the 2-kidney, 1-clip (2K1C) renal ischemia rats, where PRR shRNA treatment significantly attenuated the COX-2 expression in kidney but the Ang II levels in the renal interstitial fluid were unaffected. 38 In addition, PGE 2 augments prorenin/renin protein expression in cultured M-1 CD cells, subsequently activates PRR to stimulate the COX-2 expression and further PGE 2 synthesis, 39 then increases the expression of plasminogen activator inhibitor (PAI-1) and connecting tissue growth factor (CTGF) via EP 4 receptor and TGF-β receptor-dependent Smad pathway. 16 The binding of prorenin to PRR not only induces the non-proteolytic activation of prorenin to increase its enzymatic activity, but also triggers the activation of ERK1/2 5 .…”

“…PRR/sPRR and ELA/apelin, acting in a Yin-Yang relationship, antagonize each other: ELA/apelin inhibits the PRR/sPRR expression via inhibition of cAMP signaling, and in turn, PRR/sPRR blocks ELA/apelin expression through unknown mechanisms, with an opposite role on intrarenal renin-angiotensin system (RAS), exerting a major impact on blood pressure regulation and renal functions. 23 Activation of PRR increases the COX-2 expression via extracellular signal-regulated kinase 1/2 (ERK1/2) signaling 22 and in turn COX-2-derived PGE 2 via the prostaglandin E 2 type 1 (EP 1 ) or EP 4 receptor-mediated cAMP signaling stimulates PRR expression 18,21,53,54 ; Wnt/β-catenin signaling directly stimulates PRR expression via promoting lymphoid enhancer-binding factor 1 (LEF-1) binding to putative T cell factor (TCF)/LEF binding sites in the promoter of ATP6AP2 (ATPase, H + -transporting, lysosomal accessory protein 2) gene, 15 PRR/sPRR binds to Frizzled-8 and low-density lipoprotein receptorrelated protein 6 (LRP6) to activate Wnt/β-catenin signaling 10,65 ; COX-2-derived PGE 2 stimulates Wnt/β-catenin signaling through EP 2 or EP 4 receptors via phosphatidylinositol 3-kinase (PI3K)/AKT/glycogen synthase 3β (Gsk3β) signaling, [157][158][159] and activation of Wnt/β-catenin enhances COX-2 expression via activating LEF-1 binding to TCF/LEF binding sites in the promoter of COX-2 gene, 160,161 thus forming vicious cycles in order to achieve the sustained activation of intrarenal RAS, eventually leading to elevated blood pressure and deteriorated kidney injury. PRR also works as an accessory subunit of the V-ATPase by binding to Ac45 (ATP6AP1, ATPase, H + -transporting accessory protein 1), which requires the extracellular domain and the transmembrane domain of PRR, 65,131,132,136 controlling acid-base homeostasis, urine acidification, and cell survival.…”