One prostaglandin, three opposite effects: how PGE2 runs the urinary tract organ by organ, review proposes

Prostaglandin E2, the dominant lipid mediator produced within the wall of the urinary tract, does something chemically unusual: it pushes the bladder, the ureter, and the prostate and urethra in opposite directions. A new review in Frontiers in Physiology argues that this apparent contradiction is not a mess of organ-specific quirks but a single signaling system deployed in three organ-specific strategies, and it lays out what that organization could mean for treating overactive bladder, renal colic, and benign prostatic hyperplasia.

The review, written by a team of urology and laboratory medicine researchers from hospitals in Guizhou Province and Shanghai, synthesizes 115 publications spanning six decades, from classical organ-bath experiments to current clinical trials. Its central claim is deliberately framed as a testable working hypothesis rather than an established mechanism, and the authors are explicit about where the evidence is strong and where it is thin.

The molecular logic begins with the biosynthetic machinery. PGE2 is made from membrane phospholipids through cyclooxygenase-1 and -2 together with microsomal PGE synthase-1, an inducible enzyme functionally coupled to COX-2. In human urinary tract tissue, infection and obstruction induce COX-2 and augment PGE2 production, tying inflammation directly to altered smooth muscle behavior. Because basal output in healthy tissue is low, the authors note, drugs that block the pathway mainly change urinary tract behavior under inflammatory or obstructive conditions rather than at rest.

Reception is where the divergence becomes possible. PGE2 signals through four G protein-coupled receptor subtypes, EP1 through EP4, defined pharmacologically by the International Union of Pharmacology. Their coupling is asymmetric: EP1 engages Gq and mobilizes calcium, which is conventionally excitatory in smooth muscle; EP2 and EP4 raise intracellular cAMP through Gs, which is relaxant; and EP3 acts primarily through Gi, with splice variants that can acquire Gs or Gq competence. That split gives one ligand a ready molecular basis for producing contraction in one organ and relaxation in another, and the review argues that each organ’s dominant response follows the coupling direction of its dominant receptor subtype.

In the bladder, the strategy is excitation on two fronts, motor and sensory, distributed across a mosaic of receptor-bearing cell types. Smooth muscle from rat, macaque, and human tissue contracts to PGE2 principally through EP1- and EP3-like receptors, with contraction ranking among the most robust prostanoid effects in human detrusor. The urothelium both generates the mediator and expresses its receptors, interstitial cells of Cajal provide an amplifier for spontaneous activity, and primary afferents are sensitized within minutes of exposure. Genetic work has separated the two excitatory subtypes: EP3-deficient mice show enlarged bladder capacity and lose PGE2-evoked hyperactivity, while EP1-deficient mice show altered detrusor responses under bladder outlet obstruction, suggesting EP3 stands closer to the afferent and pacing apparatus and EP1 to the obstruction-responsive contractile response.

One mechanistic route has been characterized in detail: EP3 activation raises bladder excitability through HCN channels on interstitial cells of Cajal, supplying a path from inflammatory mediator to organ-level hyperexcitability that bypasses the nerve terminal. The urothelium is the leading candidate for the sensory transduction step, since PGE2 augments stretch-evoked ATP release via EP1/EP3 receptors, and after capsaicin desensitization the effects of intravesical PGE2 on bladder function are preserved, implicating a non-neural, likely mucosal, step. Obstruction, inflammation, denervation, and aging each reprogram the receptor phenotype, and the authors caution that the instillation model anchoring much of this work uses acute PGE2 concentrations that exceed anything the urothelium generates physiologically, so it reveals the axis’s capacity rather than replicating disease dosimetry.

The ureter inverts the strategy. Through EP2-dominated reception, PGE2 dampens tone and slows peristalsis, an arrangement that serves the organ’s mission of moving urine at low pressure. The inhibitory phenotype was documented in 1966, and the molecular address arrived only recently: in a single-center study of 25 New Zealand rabbits, PGE2 relaxed isolated ureters with an EC50 near 2 × 10⁻7 M, the EP2 antagonist PF-04418948 blocked the relaxation while the EP4 antagonist L-161,982 did not, and obstructed ureters upregulated mPGES-1 and EP2. The EP4 contribution remains an inference from coupling logic, since direct rabbit testing found EP4 blockade ineffective, and no in-vivo expulsion endpoint was measured in that study.

This inhibitory deployment is what non-steroidal anti-inflammatory drugs, the first-line analgesics for renal colic, act upon, yet the review is blunt that their mechanism remains unresolved. Trial endpoints in the clinical literature are pain scores and analgesic rescue, not ureteral motility, wall edema, or afferent discharge, so clinical success establishes that the pathway matters without establishing which branch carries the analgesic effect. Three accounts, peristaltic, hydraulic, and afferent, are pharmacologically compatible and may co-occur; the peristaltic account holds the strongest in vitro foundation but the weakest clinical logic, since restored contraction against an unrelieved obstruction should raise intraluminal pressure, and NSAIDs can themselves inhibit isolated ureteral motility. The authors propose a concrete trial design pairing standard NSAID analgesia with CT-based measurements of ureteral wall thickness and peri-ureteral edema to test the hydraulic account directly, noting that no such trial has been run.

The outflow tract is the weakest-evidenced arm. Human tissue experiments established the relaxant response early: in isolated human preparations, PGE2 contracted bladder body strips while relaxing urethral tissue from the same patients, and local application in women lowered intraurethral pressure in vivo. Rodent pharmacology has characterized an inhibitory prostanoid receptor in the rat prostate compatible with a cAMP-coupled subtype, and both COX-1 and COX-2 are expressed in the human prostate. A single tissue-comparison study reports the prostaglandin pathway detectably activated in prostate tissue from patients who failed standard medical therapy for BPH relative to treatment-responsive tissue, but the authors stress this is an association whose causal direction is untested, and no interventional trial has targeted the pathway in BPH. No subtype-resolved EP map of the human urethra exists, and female urethral prostanoid pharmacology is nearly empty.

Therapeutically, the review maps the axis onto one established success, two credible prospects, and one open frontier. Synthesis-level NSAID blockade for renal colic is standard care but subtype-blind, and the mPGES-1 experience warns that blocking one synthetic node can redirect mediator flow toward prostacyclin rather than silence it. At the receptor level, the dual EP2/EP3 agonist ONO-8055 improved voiding in rat and primate models of underactive bladder and, according to the sponsor’s unpublished pipeline disclosures, entered phase I evaluation in Europe before development was discontinued. EP2 agonism to relax the ureter is a preclinical candidate whose expulsion benefit remains untested. In overactive bladder, EP1 or EP4 antagonism has animal urodynamic support but no clinical program, and in BPH no receptor-level candidate exists at all. The authors argue that choosing a receptor subtype would approximate choosing an organ, but they concede that the matrix’s weights are inferred from function rather than measured receptor abundance, that no cross-organ, cell-resolved expression map of EP1 through EP4 exists for the urinary tract, and that ligand selectivity established in rodents does not always transfer to human tissue. Whether the triad holds, they conclude, is a matter of execution rather than of doubt, and the outflow row is the one most likely to be rewritten.

Subject of Research: How the PGE2–EP receptor axis produces opposite smooth muscle effects in the bladder, ureter, and outflow tract

Article Title: The PGE2–EP receptor axis in urinary tract smooth muscle: one signaling system, three organ-specific strategies

Article References: Su, H., Zhou, W., Ao, F., Ye, T., You, G., Yuan, D., Zhu, J., & Zhou, H. (2026). The PGE2–EP receptor axis in urinary tract smooth muscle: one signaling system, three organ-specific strategies. Frontiers in Physiology, 17, Article 1977562. https://doi.org/10.3389/fphys.2026.1977562

Image Credits: AI Generated

DOI: 10.3389/fphys.2026.1977562

Keywords: prostaglandin E2, EP receptors, urinary tract smooth muscle, overactive bladder, renal colic, NSAIDs, ureteral peristalsis, benign prostatic hyperplasia, cyclooxygenase-2, underactive bladder, detrusor, EP2 agonism