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 prostaglandin_2α (PGF_2α) 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 (mkpCCD_c14) 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 PGF_2α reduced AQP2 abundance. dDAVP increased the cellular PGD₂ and PGE₂ release and decreased the PGF_2α 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 mpkCCD_c14 cells, reduced EP4 receptor and increased EP1/FP receptor expression by dDAVP explains the differential effects of PGE₂ and PGF_2α 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.