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

• Published in: American Journal of Physiology - Renal Physiology Vol. 296; no. 5; pp. F1194 - F1201
• Main Authors: Zhang, Yue, Nelson, Raoul D, Carlson, Noel G, Kamerath, Craig D, Kohan, Donald E, Kishore, Bellamkonda K
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2009
• Subjects: Animals; Antagonist drugs; Diabetes Insipidus, Nephrogenic - chemically induced; Diabetes Insipidus, Nephrogenic - metabolism; Diabetes Insipidus, Nephrogenic - physiopathology; Diet; Dinoprostone - urine; Fluorescent Antibody Technique; Gene expression; Gene Expression - physiology; Kidney Medulla - metabolism; Kidney Tubules, Collecting - metabolism; Kidneys; Lithium; Lithium - toxicity; Male; Polyuria - chemically induced; Polyuria - metabolism; Polyuria - physiopathology; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2 - metabolism; Receptors, Purinergic P2Y1; Receptors, Purinergic P2Y2; Ribonucleic acid; RNA; Rodents; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 1931-857X; 0363-6127; 1522-1466
• 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 ( approximately 20% of controls) and a twofold increase in urinary PGE(2). When acutely challenged ex vivo with adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS), UTP, or ADP, mCD of Li-fed rats showed significantly higher increases (50-130% over control diet-fed rats) in PGE(2) 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.