Potential role of purinergic signaling in lithium-induced nephrogenic diabetes insipidus

Zhang Y, Nelson RD, Carlson NG, Kamerath CD, Kohan DE, Kishore BK. Potential role of purinergic signaling in lithium-induced nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 296: F1194-F1201, 2009. First published February 25, 2009; doi:10.1152/ajprenal.90774.2008.-Lithium (Li)-induced nephrogenic diabetes insipidus (NDI) has been attributed to the increased production of renal prostaglandin (PG)E-2. Previously we reported that extracellular nucleotides (ATP/UTP), acting through P-2y2 receptor in rat medullary collecting duct (mCD), produce and release PGE(2). Hence we hypothesized that increased production of PGE(2) in Li-induced NDI may be mediated by enhanced purinergic signaling in the mCD. Sprague-Dawley rats were fed either control or Li-added diet for 14 or 21 days. Li feeding resulted in marked polyuria and polydipsia associated with a decrease in aquaporin (AQP)2 protein abundance in inner medulla (similar to 20% of controls) and a twofold increase in urinary PGE(2). When acutely challenged ex vivo with adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S), UTP, or ADP, mCD of Li-fed rats showed significantly higher increases (50-130% over control diet-fed rats) in PGE2 production, indicating that more than one subtype of P-2y receptor is involved. This was associated with a 3.4-fold increase in P-2y4, but not P-2y2, receptor mRNA expression in the inner medulla of Li-fed rats compared with control diet-fed rats. Confocal laser immunofluorescence microscopy revealed predominant localization of both P-2y2 and P-2y4 receptors in the mCD of control or Li diet-fed rats. Together, these data indicate that in Li-induced NDI 1) purinergic signaling in the mCD is sensitized with increased production of PGE(2) and 2) P-2y2 and/or P-2y4 receptors may be involved in the enhanced purinergic signaling. Our study also reveals the potential beneficial effects of P-2y receptor antagonists in the treatment and/or prevention of Li-induced NDI.