PMID:19244398

Citation	Zhang, Y, Nelson, RD, Carlson, NG, Kamerath, CD, Kohan, DE and Kishore, BK (2009) Potential role of purinergic signaling in lithium-induced nephrogenic diabetes insipidus. Am. J. Physiol. Renal Physiol. 296:F1194-201
Abstract	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.
Links	PubMed PMC2681373 Online version:10.1152/ajprenal.90774.2008
Keywords	Animals; Diabetes Insipidus, Nephrogenic/chemically induced; Diabetes Insipidus, Nephrogenic/metabolism; Diabetes Insipidus, Nephrogenic/physiopathology; Dinoprostone/urine; Fluorescent Antibody Technique; Gene Expression/physiology; Kidney Medulla/metabolism; Kidney Tubules, Collecting/metabolism; 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; Signal Transduction/drug effects; Signal Transduction/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:AQP2	involved_in	GO:0010226: response to lithium ion	ECO:0000270: expression pattern evidence used in manual assertion		P		Seeded From UniProt	complete

References

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