title: Potential role of purinergic signaling in lithium-induced nephrogenic diabetes insipidus.
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.
authors.affiliation: Nephrology Research (151M VA SCL Health Care System, 500 Foothill Dr., Salt Lake City, UT 84148. bk.kishore@hsc.utah.edu).
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Raoul D
authors.initials: RD
authors.lastname: Nelson
authors.forename: Noel G
authors.initials: NG
authors.lastname: Carlson
authors.forename: Craig D
authors.initials: CD
authors.lastname: Kamerath
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
authors.forename: Bellamkonda K
authors.initials: BK
authors.lastname: Kishore
mesh_terms: D000818:Animals; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D015232:Dinoprostone / Q000652:urine; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000502:physiology; D007679:Kidney Medulla / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D008094:Lithium / Q000633:toxicity; D008297:Male; D011141:Polyuria / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: C546384:P2ry1 protein, rat; C546387:P2ry2 protein, rat; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; C104749:purinoceptor P2Y4; C099845:purinoceptor P2Y6; D008094:Lithium; D015232:Dinoprostone