A Vasopressin-Induced Change in Prostaglandin Receptor Subtype Expression Explains the Differential Effect of PGE2 on AQP2 Expression.

Peter M T Deen,Marleen L A Kortenoeven,Claudia Carmone,Robert A Fenton,Horst Schweer,Jack F M Wetzels,Michelle Boone,Emma T B Olesen

doi:10.3389/fphys.2021.787598

Abstract

Arginine vasopressin (AVP) stimulates the concentration of renal urine by increasing the principal cell expression of aquaporin-2 (AQP2) water channels. Prostaglandin E2 (PGE2) and prostaglandin2α (PGF2α) increase the water absorption of the principal cell without AVP, but PGE2 decreases it in the presence of AVP. The underlying mechanism of this paradoxical response was investigated here. Mouse cortical collecting duct (mkpCCDc14) cells mimic principal cells as they endogenously express AQP2 in response to AVP. PGE2 increased AQP2 abundance without desmopressin (dDAVP), while in the presence of dDAVP, PGE2, and PGF2α reduced AQP2 abundance. dDAVP increased the cellular PGD2 and PGE2 release and decreased the PGF2α release. MpkCCD cells expressed mRNAs for the receptors of PGE2 (EP1/EP4), PGF2 (FP), and TxB2 (TP). Incubation with dDAVP increased the expression of EP1 and FP but decreased the expression of EP4. In the absence of dDAVP, incubation of mpkCCD cells with an EP4, but not EP1/3, agonist increased AQP2 abundance, and the PGE2-induced increase in AQP2 was blocked with an EP4 antagonist. Moreover, in the presence of dDAVP, an EP1/3, but not EP4, agonist decreased the AQP2 abundance, and the addition of EP1 antagonists prevented the PGE2-mediated downregulation of AQP2. Our study shows that in mpkCCDc14 cells, reduced EP4 receptor and increased EP1/FP receptor expression by dDAVP explains the differential effects of PGE2 and PGF2α on AQP2 abundance with or without dDAVP. As the V2R and EP4 receptor, but not the EP1 and FP receptor, can couple to Gs and stimulate the cyclic adenosine monophosphate (cAMP) pathway, our data support a view that cells can desensitize themselves for receptors activating the same pathway and sensitize themselves for receptors of alternative pathways.

Highlights

To prevent dehydration, an adequate maintenance of water homeostasis is essential
To analyze the effect of Prostaglandin E2 (PGE2) on the AQP2 expression, mpkCCDc14 cells were grown to confluence for 8 days, either with or without 1 nM of the vasopressin type-2 receptor (V2R) agonist dDAVP for the last 4 days and with or without 1 μM PGE2 during the last 48 h
Prostaglandin E2 reduce the Arginine vasopressin (AVP)-stimulated water reabsorption in the collecting duct (Hebert et al, 1990; Nadler et al, 1992), while in the absence of AVP, ex vivo water permeability is increased by PGE2 (Sakairi et al, 1995)

Summary

Introduction

An adequate maintenance of water homeostasis is essential. In this process, the kidney plays a critical role. Besides AVP, several other signaling molecules regulate the water balance by antagonizing the AVP-induced water transport (Boone and Deen, 2008) One such group of molecules is the prostaglandins (Figure 1). Prostaglandins can bind to their unique G-protein-coupled receptors (i.e., DP, FP, IP, and TP) or to one or more of four different PGE2 receptors (i.e., EP1, EP2, EP3, and EP4) Some of these receptors (i.e., DP, EP2, EP4, and IP) are Gs-coupled and increase intracellular cAMP levels when activated, whereas others are coupled to Gi (i.e., EP3 and FP), reducing the cAMP synthesis, and/or Gq (i.e., EP1, FP, and TP), inducing calcium mobilization (Breyer et al, 1998; Hebert et al, 2005; Hao and Breyer, 2008)

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Conclusion