Is There a Role for PGE2 in Urinary Concentration?

Abstract

Prostanoids are prominent, yet complex, components in the maintenance of body water homeostasis. Recent functional and molecular studies have revealed that the local lipid mediator PGE2 is involved both in water excretion and absorption. The biologic actions of PGE2 are exerted through four different G-protein-coupled receptors; designated EP1-4, which couple to separate intracellular signaling pathways. Here, we discuss new developments in our understanding of the actions of PGE2 that have been uncovered utilizing receptor specific agonists and antagonists, EP receptor and PG synthase knockout mice, polyuric animal models, and the new understanding of the molecular regulation of collecting duct water permeability. The role of PGE2 in urinary concentration comprises a variety of mechanisms, which are not fully understood and likely depend on which receptor is activated under a particular physiologic condition. EP3 and microsomal PG synthase type 1 play a role in decreasing collecting duct water permeability and increasing water excretion, whereas EP2 and EP4 can bypass vasopressin signaling and increase water reabsorption through two different intracellular signaling pathways. PGE2 has an intricate role in urinary concentration, and we now suggest how targeting specific prostanoid receptor signaling pathways could be exploited for the treatment of disorders in water balance. The neurohypophyseal hormone, vasopressin (VP), is a major regulator of renal water excretion, predominantly through the seven trans-membrane receptor (7TMR) V2R. It binds to Gas, inducing the cAMP second messenger system, resulting in increased NaCl absorption by the thick ascending limb and increased urea transport in the inner medullary collecting ducts (IMCDs). [1][2][3] In addition, VP induces accumulation of the water channel aquaporin-2 (AQP2) in the rate-limiting apical plasma membrane of collecting duct (CD) principal cells, 4 a process that involves a diverse range of post-translational modifications including phosphorylation of AQP2. 5 Thus, VP increases the osmotic gradient for water transport and the water permeability (Pf) of the CD simultaneously.In addition to systemic hormones, local regulatory factors play a role in the CD, of which PGE2 (Figure 1) is the focus of this review. 6-9 PGE2 has a diverse range of biologic actions elicited by four different 7TMRs. The renal localization of EP receptors and intracellular signaling pathways are diverse (Table 1). Here, we propose that urinary concentration does not rely exclusively on fluctuations in plasma VP concentrations, but that the locally derived lipid mediator, PGE2, plays an important role in regulating water excretion. PGE2 IN THE MODULATION OF URINARY CONCENTRATING MECHANISMSThe ability of PGE2 to modulate the effects of VP in the CD has been described in a range of experimental studies and discussed in previous reviews. [36][37][38][39] The present focus is on understanding the mechanisms for this effect, and on recent in vivo studies elucidating the role of P...

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