Osmotic reabsorption of water through aquaporin-2 (AQP2) in the inner medulla is largely dependent on the urea concentration gradients generated by urea transporter (UT) isoforms. Vasopressin (AVP) increases expression of both AQP2 and UT-A isoforms. Activation of the P2Y2 receptor (P2Y2-R) in the medullary collecting duct inhibits AVP-induced water flow. To gain further insights into the overarching effect of purinergic signaling on urinary concentration, we compared the protein abundances of AQP2 and UT-A isoforms between P2Y2-R knockout (KO) and wild type (WT) mice under basal conditions and following AVP administration. Under basal conditions (gel diet for 10 days) KO mice concentrated urine to a significantly higher degree, with 1.8-, 1.66- and 1.29-fold higher protein abundances of AQP2, UT-A1 and UT-A2 as compared to WT, despite comparable circulating AVP levels in both groups. Infusion of dDAVP (desmopressin; 1 ng/h, sc) for 5 days resulted in 2.14-, 2.6- and 2.22-fold higher protein abundances of AQP2, AQP3 and UT-A1 respectively in the inner medullas of KO mice as compared to the WT mice. In response to acute (45 min) stimulation by AVP (0.2 unit/mouse, sc) UT-A1 protein increased by 1.39- and 1.54-fold in WT and KO mice, respectively. These data suggest that genetic deletion of P2Y2-R results in increased abundances of key proteins involved in urinary concentration in the inner medulla, both under basal conditions and following AVP administration. Thus, purinergic regulation may play a potential overarching role in balancing the effect of AVP on urinary concentration mechanism.