Altered expression of COX-1, COX-2, and mPGES in rats with nephrogenic and central diabetes insipidus

Kotnik, Primož; Nielsen, Jens Perch; Kwon, Tae‐Hwan; Kržišnik, Ciril; Frøkiær, Jørgen; Nielsén, Sören

doi:10.1152/ajprenal.00114.2004

Cited by 65 publications

(43 citation statements)

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“…Presumably as a result of the toxic effect of lithium on principal cells, chronic lithium therapy (Ͼ4 wk in rats) further results in a decreased number of principal cells to the benefit of intercalated cells (39), which also will contribute to a reduced dDAVP-induced cAMP generation in kidneys of rats that had lithium-induced NDI. Recently, cyclo-oxygenase 2 (COX2) expression was suggested to be involved in lithiuminduced NDI (40), but this was debated by others (41). Although our study does not exclude a role of COX-2 in development of lithium-induced NDI, the lithium-induced AQP2 downregulation in our mpkCCD cells, which are grown in the absence of COX2-producing interstitial cells, indicate that COX2-derived prostaglandins are not necessary for lithiuminduced NDI development.…”

Section: Lithium-induced Ndi Developmentcontrasting

confidence: 64%

Development of Lithium-Induced Nephrogenic Diabetes Insipidus Is Dissociated from Adenylyl Cyclase Activity

Li¹,

Shaw²,

Kamsteeg³

et al. 2006

Journal of the American Society of Nephrology

100

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In antidiuresis, vasopressin (AVP) occupation of V2 receptors in renal collecting ducts activates adenylyl cyclase, resulting in increased intracellular cAMP levels, which activates protein kinase A (PKA). PKA phosphorylates both the cAMP responsive element binding protein, which induces aquaporin-2 (AQP2) transcription, and AQP2, which then is translocated to the apical membrane, allowing urine concentration. Lithium treatment often causes nephrogenic diabetes insipidus (NDI), which coincides with decreased AQP2 expression and which generally is ascribed to reduced adenylyl cyclase activity. However, the underlying mechanism by which lithium causes NDI is poorly understood. This study demonstrated that the mouse cortical collecting duct mpkCCD c14 cells are a good model; the deamino-8 D-arginine vasopressin (dDAVP)-induced endogenous AQP2 expression and plasma membrane localization was time-dependently reduced by treatment with clinically relevant lithium concentrations. Lithium did not affect AQP2 stability but decreased its mRNA levels. Surprising, the effect of lithium was cAMP independent; it did not alter AVP-stimulated cAMP production or PKA-dependent phosphorylation of AQP2 or cAMP responsive element binding protein. In vivo, kidney tissue of rats with lithium-induced NDI indeed generated less dDAVP-induced cAMP than that of controls, but this could be due to elevated blood AVP levels in rats with lithium-induced NDI. Indeed, Brattleboro rats, which lack endogenous AVP, with clamped blood dDAVP levels, showed no difference in dDAVP-generated cAMP generation between kidneys of rats with lithium-induced NDI and control rats. In conclusion, the first proper cell model to study lithium-induced NDI was developed, and it was demonstrated that the lithium-induced downregulation of AQP2 and development of NDI occur independent of adenylyl cyclase activity in vitro and in vivo.

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Section: Lithium-induced Ndi Developmentcontrasting

confidence: 64%

Development of Lithium-Induced Nephrogenic Diabetes Insipidus Is Dissociated from Adenylyl Cyclase Activity

Li¹,

Shaw²,

Kamsteeg³

et al. 2006

Journal of the American Society of Nephrology

100

View full text Add to dashboard Cite

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“…Increased expression of cyclooxygenases (COX-1 and COX-2) in Li-induced NDI has been implicated in the increased production of PGE 2 (30,42). However, the availability of free arachidonic acid, the substrate, itself is considered by many investigators as the initial and often the rate-limiting step in the production of PGE 2 (4,22,37).…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Nelson²,

Carlson³

et al. 2009

American Journal of Physiology-Renal Physiology

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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...

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“…All three effects are blunted in BB rats, 87 but PGE2 excretion is restored in response to VP. 88 Under normal conditions, BB rats also display increased COX-1, COX-2, and mPGES in response to VP 89 and a variety of COX-2 inhibitors severely impair urine concentration in normal rats after water deprivation. 81 Together, these results suggest a role for PGE2 in the kidney's response to dehydration; potential mechanisms are summarized in Figure 3.…”

Section: An Emerging Role For Pge2 In Concentrating the Urinementioning

confidence: 99%

Is There a Role for PGE2 in Urinary Concentration?

Olesen

Fenton

2013

Journal of the American Society of Nephrology

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Prostanoids are prominent, yet complex, components in the maintenance of body water homeostasis. Recent functional and molecular studies have revealed that the local lipid mediator PGE2 is involved both in water excretion and absorption. The biologic actions of PGE2 are exerted through four different G-protein-coupled receptors; designated EP1-4, which couple to separate intracellular signaling pathways. Here, we discuss new developments in our understanding of the actions of PGE2 that have been uncovered utilizing receptor specific agonists and antagonists, EP receptor and PG synthase knockout mice, polyuric animal models, and the new understanding of the molecular regulation of collecting duct water permeability. The role of PGE2 in urinary concentration comprises a variety of mechanisms, which are not fully understood and likely depend on which receptor is activated under a particular physiologic condition. EP3 and microsomal PG synthase type 1 play a role in decreasing collecting duct water permeability and increasing water excretion, whereas EP2 and EP4 can bypass vasopressin signaling and increase water reabsorption through two different intracellular signaling pathways. PGE2 has an intricate role in urinary concentration, and we now suggest how targeting specific prostanoid receptor signaling pathways could be exploited for the treatment of disorders in water balance. The neurohypophyseal hormone, vasopressin (VP), is a major regulator of renal water excretion, predominantly through the seven trans-membrane receptor (7TMR) V2R. It binds to Gas, inducing the cAMP second messenger system, resulting in increased NaCl absorption by the thick ascending limb and increased urea transport in the inner medullary collecting ducts (IMCDs). [1][2][3] In addition, VP induces accumulation of the water channel aquaporin-2 (AQP2) in the rate-limiting apical plasma membrane of collecting duct (CD) principal cells, 4 a process that involves a diverse range of post-translational modifications including phosphorylation of AQP2. 5 Thus, VP increases the osmotic gradient for water transport and the water permeability (Pf) of the CD simultaneously.In addition to systemic hormones, local regulatory factors play a role in the CD, of which PGE2 (Figure 1) is the focus of this review. 6-9 PGE2 has a diverse range of biologic actions elicited by four different 7TMRs. The renal localization of EP receptors and intracellular signaling pathways are diverse (Table 1). Here, we propose that urinary concentration does not rely exclusively on fluctuations in plasma VP concentrations, but that the locally derived lipid mediator, PGE2, plays an important role in regulating water excretion. PGE2 IN THE MODULATION OF URINARY CONCENTRATING MECHANISMSThe ability of PGE2 to modulate the effects of VP in the CD has been described in a range of experimental studies and discussed in previous reviews. [36][37][38][39] The present focus is on understanding the mechanisms for this effect, and on recent in vivo studies elucidating the role of P...

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Altered expression of COX-1, COX-2, and mPGES in rats with nephrogenic and central diabetes insipidus

Cited by 65 publications

References 50 publications

Development of Lithium-Induced Nephrogenic Diabetes Insipidus Is Dissociated from Adenylyl Cyclase Activity

Development of Lithium-Induced Nephrogenic Diabetes Insipidus Is Dissociated from Adenylyl Cyclase Activity

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

Is There a Role for PGE2 in Urinary Concentration?

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