Potential involvement of P2Y2 receptor in diuresis of postobstructive uropathy in rats

Zhang Y, Kohan DE, Nelson RD, Carlson NG, Kishore BK. Potential involvement of P2Y(2) receptor in diuresis of postobstructive uropathy in rats. Am J Physiol Renal Physiol 298: F634-F642, 2010. First published December 9, 2009; doi:10.1152/ajprenal.00382.2009.-AVP resistance of the medullary collecting duct (mCD) in postobstructive uropathy (POU) has been attributed to increased production of PGE(2). P2Y(2) receptor activation causes production of PGE(2) by the mCD. We hypothesize that increased P2Y(2) receptor expression and/or activity may contribute to the diuresis of POU. Sprague-Dawley rats were subjected to bilateral ureteral obstruction for 24 h followed by release (BUO/R, n = 17) or sham operation (SHM/O, n = 15) and euthanized after 1 wk or 12 days. BUO/R rats developed significant polydipsia, polyuria, urinary concentration defect, and increased urinary PGE(2) and decreased aquaporin-2 protein abundance in the inner medulla compared with SHM/O rats. After BUO/R, the relative mRNA expression of P2Y(2) and P2Y(6) receptors was increased by 2.7-and 4.9-fold, respectively, without significant changes in mRNA expression of P2Y(1) or P2Y(4) receptor. This was associated with a significant 3.5-fold higher protein abundance of the P2Y(2) receptor in BUO/R than SHM/O rats. When freshly isolated mCD fractions were challenged with different types of nucleotides (ATP gamma S, ADP, UTP, or UDP), BUO/R and SHM/O rats responded to only ATP gamma S and UTP and released PGE(2), consistent with involvement of the P2Y(2), but not P2Y(6), receptor. ATP gamma S-or UTP-stimulated increases in PGE(2) were much higher in BUO/R (3.20- and 2.28-fold, respectively, vs. vehicle controls) than SHM/O (1.68- and 1.30-fold, respectively, vs. vehicle controls) rats. In addition, there were significant 2.4- and 2.1-fold increases in relative mRNA expression of prostanoid EP1 and EP3 receptors, respectively, in the inner medulla of BUO/R vs. SHM/O rats. Taken together, these data suggest that increased production of PGE(2) by the mCD in POU may be due to increased expression and activity of the P2Y(2) receptor. Increased mRNA expression of EP1 and EP3 receptors in POU may also help accentuate PGE(2)-induced signaling in the mCD.