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

Abstract

Zhang Y, Nelson RD, Carlson NG, Kamerath CD, Kohan DE, Kishore BK. Potential role of purinergic signaling in lithiuminduced 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)E2. Previously we reported that extracellular nucleotides (ATP/UTP), acting through P 2y2 receptor in rat medullary collecting duct (mCD), produce and release PGE2. 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 (ϳ20% of controls) and a twofold increase in urinary PGE2. When acutely challenged ex vivo with adenosine 5Ј-O-(3-thiotriphosphate) (ATP␥S), 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 P2y4, but not P2y2, 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 P2y2 and P2y4 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 PGE2 and 2) P2y2 and/or P2y4 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. collecting duct; P 2 receptors; extracellular nucleotides; prostaglandin E 2; cyclooxygenases; bipolar disorder; neurodegeneration; rat LITHIUM (Li) has been in clinical use for about half a century, mostly for the treatment of bipolar disorder, which affects up to 2% of the US population (33), with double the incidence in veterans. Mental depression and substance abuse, which are often encountered in posttraumatic stress disorder patients, such as war veterans, are known to predispose them to bipolar disorders. Despite the advent of newer drugs for bipolar disorders, Li is still an important medication in the psychiatric treatment regimen by virtue of the significantly lower suicidal risk in Li-treated patients (3). In addition, the advances in the pharmacotherapeutics of bipolar disorder over the past 10 -15 yr have been predominantly in terms of tolerability and safety, with no new treatments being demonstrated to be more effective than Li (38). Furthermore, recent studies unraveled the neuroprotective effect of Li, thus making it a potential drug for the treatment of acute brain injury (e.g., stroke...

Attenuation of lithium-induced natriuresis and kaliuresis in P2Y2receptor knockout mice

“…This was found to occur without any alterations in serum or renal medullary lithium levels (41,42). The mechanisms are not completely understood, but our study suggested reduced PGE 2 signaling through the EP 3 receptor might play a role by preserving cAMP generation and thus protecting collecting duct AQP2 protein in the renal medulla (42).…”

“…Recently, we (41,42) have shown that mice with genetic deletion of P2Y 2 R have significant resistance to the development of lithium-induced polyuria. This was found to occur without any alterations in serum or renal medullary lithium levels (41,42).…”

Prasugrel suppresses development of lithium-induced nephrogenic diabetes insipidus in mice

“…Thus, it appears that the autocrine and/or paracrine actions of extracellular nucleotides through P2Y receptors constitute tonic inhibitory effect on water and sodium reabsorption mediated by the AVP and aldosterone. Based on this deduction, we posited that the same actions of extracellular nucleotides mediated by P2Y receptors may also contribute to the development of collecting duct resistance to AVP often seen in acquired nephrogenic diabetes insipidus (NDI), such as the one induced by chronic lithium administration for the treatment of bipolar disorder [11][12][13]. Accordingly, we demonstrated that genetic deletion of P2Y 2 receptor confers significant resistance for the development of lithium-induced NDI [14,15].…”

Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus

“…However, despite major progress, no clear consensus regarding the "trigger" for the onset of the condition exists. For example, data from large-scale proteomic (7) and metabonomic approaches (8), coupled with targeted studies in animal models and gene-modified mice, have illustrated changes in renal prostaglandins (9); purinergic signaling (10); and the activity of glycogen synthase kinase 3 (GSK3) (11), PKC (12), MAPKs, ERKs ERK1/2 and P38α (13), and the phosphatidylinositol signalPsychiatric patients treated with lithium (Li + ) may develop nephrogenic diabetes insipidus (NDI). Although the etiology of Li + -induced NDI (Li-NDI) is poorly understood, it occurs partially due to reduced aquaporin-2 (AQP2) expression in the kidney collecting ducts.…”