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

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.

Effects of phenylbutazone, firocoxib, and dipyrone on the diuretic response to furosemide in horses

“…8 However, inhibition of these hemodynamic responses to furosemide administration was considered unlikely to contribute substantially to attenuation of furosemide-induced diuresis. 4,27 Currently, this complex interaction of PGE 2 with its multiple receptors is incompletely understood but in studies examining the effects of NSAIDs on furosemide-induced diuresis, NSAIDs attenuate diuresis by up to 50%. 3,4,6 Our study was not designed to determine the mechanism(s) by which NSAIDs attenuate furosemide-induced diuresis; thus, the pro-…”

“…PGE 2 action on EP4 and EP2 receptors increase intracellular cAMP, promoting phosphorylation, translocation, and expression of aquaporin 2 (AQP2), thereby increasing collecting duct water permeability and urine concentration. In contrast, PGE 2 action on EP1 and EP3 receptors appears to downregulate AQP2 function by increasing intracellular Ca ++ and attenuating cAMP production, respectively, leading to diuresis 4,27 . Currently, this complex interaction of PGE 2 with its multiple receptors is incompletely understood but in studies examining the effects of NSAIDs on furosemide‐induced diuresis, NSAIDs attenuate diuresis by up to 50% 3,4,6 …”

Prostaglandin E2, Osmoregulation, and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

“…2 PGE2 can either increase or decrease water reabsorption depending on the E-prostanoid (EP) receptor subtypes that are expressed and whether vasopressin is present or absent. 3,4 PGE2 is rapidly metabolized in the kidney to inactive PGE2 metabolite (PGEM) and excreted in urine as both PGE2 and PGEM. 5 Patients with autosomal dominant polycystic kidney disease (ADPKD) develop a urinary concentrating defect early in the course of the disease.…”