mPGES-1 deletion potentiates urine concentrating capability after water deprivation

Liu, Gang; Downton, Maicy; Dong, Zheng; Zhang, Aihua; Yang, Tianxin

doi:10.1152/ajprenal.00508.2011

Cited by 21 publications

(18 citation statements)

References 40 publications

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“…Any role of plasma VP in these responses should be interpreted with some caution. The measured VP levels are exceptionally high in both studies, with a 10-fold difference in levels between the studies, 78,80 suggesting that acute increases in plasma VP during stress responses (due to e.g., anesthesia) could mask potential differences between WT and mPGES-1 KO mice.…”

Section: A Role For Renal Prostanoids In Physiologic Water Excretionmentioning

confidence: 89%

“…After a 24-hour water deprivation, despite blunted VP release, mPGES-1 KO mice displayed potentiated urinary concentrating ability alongside augmented increases in AQP2, UT-A1, and UT-A3 expression. 80 Furthermore, urinary excretion of PGE2 increased in WTmice alongside kidney mRNA encoding COX-2 expression, but no change was observed in mRNA encoding mPGES. Although protein levels were not assessed, this suggests that COX-2, but not mPGES-1, is rate limiting for dehydration-induced increases in PGE2 synthesis.…”

Section: A Role For Renal Prostanoids In Physiologic Water Excretionmentioning

confidence: 96%

“…A striking observation is that although mPGES-1 KO mice have an increased ability to concentrate their urine, 80 treatment of rats with several different types of COX inhibitors reduced the concentrating ability of rats after water restriction. 81 mPGES-1 is the main PG synthase of the papillary interstitial cells, 6 and mPGES-1 KO mice would still synthesize PGE2 through COX-1 and cPGES in the collecting duct, where PGE2 may increase Pf.…”

Section: A Role For Renal Prostanoids In Physiologic Water Excretionmentioning

confidence: 99%

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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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Section: A Role For Renal Prostanoids In Physiologic Water Excretionmentioning

confidence: 89%

Section: A Role For Renal Prostanoids In Physiologic Water Excretionmentioning

confidence: 96%

Section: A Role For Renal Prostanoids In Physiologic Water Excretionmentioning

confidence: 99%

See 1 more Smart Citation

Is There a Role for PGE2 in Urinary Concentration?

Olesen

Fenton

2013

Journal of the American Society of Nephrology

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“…In contrast, the accompanying anemia was enhanced in mPGES-1-deficient mice due to an impaired upregulation of erythropoietin levels. Moreover, deletion of mPGES-1 reduced the diuretic response to acute water loading [23] and increased urine concentration after water deprivation [24] while diminishing natriuresis [25]. To which extend mPGES-1 is required to excrete an acute enteral load of sodium chloride and whether this has impact on the blood pressure is controversially discussed [13,20].…”

Section: Page 9 Of 59mentioning

confidence: 99%

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

Koeberle

Werz

2015

Biochemical Pharmacology

112

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“…The present study for the first time demonstrates that mPGES-1-derived PGE 2 serves as a key regulator of urinary Na ϩ excre- tion during WD. In a separate study (23), we demonstrate that mPGES-1 deletion enhances urine concentrating capability after WD via stimulation of renal aquaporin-2 expression. The dual role of PGE 2 facilitates the separate but coordinated regulation of salt and water handling at least during WD.…”

Section: Discussionmentioning

confidence: 68%

mPGES-1-derived PGE₂ mediates dehydration natriuresis

Liu

Sun

Kakizoe

et al. 2013

American Journal of Physiology-Renal Physiology

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is a natriuretic factor whose production is elevated after water deprivation (WD) but its role in dehydration natriuresis is not well-defined. The goal of the present study was to investigate the role of microsomal prostaglandin E synthase-1 (mPGES-1) in dehydration natriuresis. After 24-h WD, wild-type (WT) mice exhibited a significant increase in 24-h urinary Na ϩ excretion accompanied with normal plasma Na ϩ concentration and osmolality. In contrast, WD-induced elevation of urinary Na ϩ excretion was completely abolished in mPGES-1 knockout (KO) mice in parallel with increased plasma Na ϩ concentration and a trend increase in plasma osmolality. WD induced a 1.8-fold increase in urinary PGE2 output and a 1.6-fold increase in PGE2 content in the renal medulla of WT mice, both of which were completely abolished by mPGES-1 deletion. Similar patterns of changes were observed for urinary nitrate/nitrite and cGMP. The natriuresis in dehydrated WT mice was associated with a significant downregulation of renal medullary epithelial Na channel-␣ mRNA and protein, contrasting to unaltered expressions in dehydrated KO mice. By quantitative RT-PCR, WD increased the endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS expressions in the renal medulla of WT mice by 3.9-, 1.48-, and 2.6-fold, respectively, all of which were significantly blocked in mPGES-1 KO mice. The regulation of eNOS expression was further confirmed by immunoblotting. Taken together, our results suggest that mPGES-1-derived PGE2 contributes to dehydration natriuresis likely via NO/ cGMP. mPGES-1; PGE2; dehydration natriuresis; cGMP; nitric oxide DEHYDRATION LEADS TO THE DEPLETION of plasma volume and the increase of body fluid osmolality. Such changes trigger the homeostatic response to conserve the fluids through the thirst mechanism, vasopressin release, and potentiated renal reabsorption. During the early stage of dehydration, an important physiological response is an acute increase in urinary Na ϩ excretion, a phenomenon termed dehydration natriuresis. This response will help prevent the further rise of plasma Na ϩ concentration and extracellular tonicity. Dehydration natriuresis has been demonstrated in humans as well as in other mammalian species, including dog, sheep, rat, and mouse (1,7,18,28,31,33,36,37). A number of factors such as neurohypophysial hormones and serum-and glucocorticoid-inducible kinase (Sgk1) are implicated in mediating dehydration natriuresis but the precise mechanism remains unclear.PGE 2 is a major prostanoid in the kidney and possesses natriuretic property owing to its ability to inhibit Na ϩ transport in the distal nephron (3, 6, 39, 43). The elevation of urinary PGE 2 in response to dehydration accompanied with increased renal medullary cyclooxygenase (COX)-2 expression has also been well-demonstrated (29,41,47). However, the functional implication of dehydration-induced renal PGE 2 synthesis is still incompletely understood.To date, three PGE synthases (PGES) have been cloned, including microsomal PGE...

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mPGES-1 deletion potentiates urine concentrating capability after water deprivation

Cited by 21 publications

References 40 publications

Is There a Role for PGE2 in Urinary Concentration?

Is There a Role for PGE2 in Urinary Concentration?

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

mPGES-1-derived PGE₂ mediates dehydration natriuresis

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mPGES-1 deletion potentiates urine concentrating capability after water deprivation

Cited by 21 publications

References 40 publications

Is There a Role for PGE2 in Urinary Concentration?

Is There a Role for PGE2 in Urinary Concentration?

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

mPGES-1-derived PGE2 mediates dehydration natriuresis

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Resources

About

mPGES-1-derived PGE₂ mediates dehydration natriuresis