The EP4 Receptor for Prostaglandin E2 in Glomerular Disease

Abstract

Prostanoids generated by the metabolism of arachidonic acid through the cyclooxygenase (COX) pathway have diverse functions in health and disease. 1 The kidney is prominent among the physiologic systems affected by these ubiquitous mediators. Along with effects to modulate renal blood flow, GFR, and sodium excretion, prostanoids affect the function of the glomerular filtration barrier. This is illustrated by clinical studies showing that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX enzymes, attenuate the levels of proteinuria in patients with glomerular diseases. 2,3 Because NSAIDs block production of all prostanoids, the specific prostanoids influencing glomerular function in this setting cannot be discerned. Moreover, because NSAIDs frequently cause adverse effects in patients with kidney disease, including acute deterioration in GFR and exacerbation of hypertension, this approach to antiproteinuric therapy has limited applications.In experimental models of glomerular disease, a number of studies have indicated beneficial effects of more specific pharmacologic inhibitors that block individual prostanoid synthetic pathways or receptors. More recently, this issue has been explored using modern molecular genetics. For example, Harris and associates 4,5 showed that overexpression of the inducible COX isoform, COX2, in podocytes of transgenic mice enhances susceptibility to glomerular injury caused by adriamycin or puromycin. This was due, at least in part, to exaggerated production of thromboxane A 2 and activation of the thromboxane-prostanoid (TP) receptor. 6 These findings are consistent with older studies showing efficacy of thromboxane synthase inhibitors and TP receptor antagonists in experimental models such as adriamycin nephropathy 7 and murine lupus nephritis. 8 In this issue of JASN, Stitt-Cavanagh et al. 9 implicate another prostanoid pathway in glomerular disease: Prostaglandin E 2 (PGE 2 ) acting through its EP4 receptor. This finding is surprising from at least two perspectives. First, in the studies of Harris and associates, deletion of EP4 receptors from podocytes had no effect on proteinuria and kidney injury in mice also overexpressing COX2. 6 Second, the EP4 receptor has long been considered to have beneficial and protective effects in kidney disease and hypertension.Once COX and PGE synthases form PGE 2 through the successive metabolism of arachidonic acid, it elicits its biological effects through a family of G protein-coupled receptors. These receptors, by convention designated EP (for E-prostanoid) receptors, are divided into four distinct pharmacologic classes: EP1 through 4. 10,11 The EP4 receptor signals through Gs proteins and adenylyl cyclase. 11 Because of the linkage between enhanced formation of cAMP and relaxation of bronchial and vascular smooth muscle, the EP4 receptor has been classically considered a relaxant receptor. 11 In the kidney, vasodilator actions of PGE 2 , likely mediated by the EP4 receptor, are linked to protection of renal blood flow during sta...

The Effect of Interleukin-4 and Dexamethasone on RNA-Seq-Based Transcriptomic Profiling of Human Podocytes: A Potential Role in Minimal Change Nephrotic Syndrome

“…Figure 9 summarizes the proposed mechanism of IL-4-induced podocyte injury involving these genes and pathways implicated in GO analyses. Of the two positively expressed DEGs, PTGER4 (prostaglandin E receptor 4) encodes for prostaglandin (PG) E4, and PGE2 is known to induce cyclooxygenase (COX)-2 expression in podocytes via the PGE4 receptor [35,36]. Enhanced expression of E-prostanoid receptor 4 (EP4) in cultured podocytes was shown to negatively affect podocyte adapta-tion to mechanical stretch [37], while the inhibition of EP4 attenuated the development of nephropathy in rodent models [38,39].…”

Esrrγa regulates nephron and ciliary development by controlling prostaglandin synthesis

“…Prostaglandins have been established as key bioactive molecules in various tissues, and implicated in disease states relating to inflammation, vascular development, cardiac injury, regeneration and kidney disease ( FitzSimons et al, 2020 ; Lannoy et al, 2020 ; Liu et al, 2023 ; Marra et al, 2019a ; Sparks and Coffman, 2010 ; Ugwuagbo et al, 2019 ). In some models, blockade of a prostaglandin receptor (EP4) can improve cystic disease states, yet PGE 2 has also been implicated as an essential factor of cilia outgrowth and proper nephron patterning, which together point to the importance of proper spatiotemporal control of prostaglandin dosage ( Chambers et al, 2020b ; Jin et al, 2014 ; Lannoy et al, 2020 ; Marra et al, 2019a ; Poureetezadi et al, 2016 ).…”

Esrrγa regulates nephron development and ciliogenesis by controlling prostaglandin synthesis and cooperation with Ppargc1a

“…Prior to this work, prostaglandins have been established as key bioactive molecule in various tissues, and implicated in disease states relating to inflammation, vascular development, cardiac injury, and kidney disease (Lannoy et al, 2020, FitzSimons et al, 2020, Marra et al, 2019a, Sparks and Coffman, 2010, Ugwuagbo et al, 2019. In some models, blockade of a prostaglandin receptor (EP4) can improve cystic disease states, yet PGE2 has also been implicated as an essential factor of cilia outgrowth and proper nephron patterning, which together point to the importance of proper spatiotemporal control of prostaglandin dosage.…”