Increased urinary concentrating ability of P2Y2 receptor null mice is associated with marked increase in protein abundances of AQP2 and UT‐A in renal medulla

Abstract

Agonist (ATP/UTP) activation of P2Y2 receptor (P2Y2-R) in the medullary collecting duct (mCD) decreases arginine vasopressin (AVP)-induced water flow, and releases PGE2, a potent inhibitor of AVP action on mCD. Hence, we analyzed age and sex matched P2Y2-R null (KO) and wild (WT) mice (N = 6/genotype; courtesy of Dr. Beverly Koller) after subjecting them to metabolic balance by feeding a gel diet containing fixed (70%) water content for 10 days. The water balance data obtained on the last three days were averaged. As compared to the WT mice the KO mice showed significantly less water consumption (− 11%; P < 0.04) and urine output (−32%; P < 0.02), and higher urinary osmolality (+ 38%; P < 0.002). There were no significant differences in total osmolar excretion or serum osmolality or AVP levels. Western analysis of renal medullas showed significant increases in mean protein abundances of AQP2 water channel (1.8-fold; P < 0.006), UT-A (~2-fold; P < 0.02), and a tendency for UT-B (+14%; P = 0.09) urea transporter isoforms. These data indicate that deletion of P2Y2-R apparently sensitizes mCD to the action of circulating AVP, resulting in direct increase in protein abundances of AQP2 and indirect increase in the UT-A, the key players in urinary concentration. Thus these findings underscore our hypothesis that in vivo P2Y2-R plays a significant role in modulating the mCD function.