Dominant Role of Prostaglandin E2 EP4 Receptor in Furosemide-Induced Salt-Losing Tubulopathy

Nüsing, Rolf M.; Treude, Antje; Weißenberger, Christian; Jensen, Boye L.; Bek, Martin; Wagner, Charlotte; Narumiya, Shuh; Seyberth, Hannsjörg W.

doi:10.1681/asn.2004070556

Cited by 51 publications

(42 citation statements)

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“…EP 2 and EP 4 receptor stimulation generally increases cAMP generation and signaling in the kidney. This would therefore be predicted to reduce sodium excretion and would apparently conflict with reports that EP 2 or EP 4 receptor blockade reduces sodium excretion [28,39]; however, a solution may be found in our recent studies. We showed that the cAMP-dependent pathway decreased the phosphorylation of two key regulator kinases that enhance ENaC activity, Akt and serum-and glucocorticoid-regulated kinase-1.…”

Section: Pharmacological Mechanisms Of Nsaids On Fluid and Blood Prescontrasting

confidence: 76%

“…Chen et al [27] demonstrated that renal medullary EP 2 receptors participated in natriuresis in mice during a high-salt diet. Nüsing et al [28] generated a mouse model of HPS/aBS using prolonged administration of furosemide. They reported the involvement of EP 1 , EP 3 , and especially EP 4 receptor activation in the enhanced natriuresis in this model.…”

Section: Pharmacological Mechanisms Of Nsaids On Fluid and Blood Presmentioning

confidence: 99%

“…While it is well established that EP 2 or EP 4 receptors promote vasodilatation, renin release, and reduced urinary volume by activating the cAMP-PKA pathway in vascular endothelial cells, JG granular cells, and collecting duct cells, respectively, the molecular mechanisms underlying the natriuretic actions of EP 2 or EP 4 receptors are not so well investigated. It is hard to predict the overall effects of EP 2 or EP 4 agonists on fluid and BP regulation, although a beneficial role of the EP 2 and EP 4 receptors can be anticipated from studies in EP 2 receptor-deficient mice that had salt-sensitive hypertension, [39] and where EP 4 receptor blockade moderated salt and water excretion [28]. The cAMP/PKA pathway activated the amiloride-sensitive epithelial sodium channel (ENaC) and sodium-potassium adenosine triphosphatase by promoting the trafficking of these proteins to the cell membrane in collecting duct cells [41,42].…”

Section: Pharmacological Mechanisms Of Nsaids On Fluid and Blood Presmentioning

confidence: 99%

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Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs

et al. 2011

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The antipyretic and analgesic actions of nonsteroidal anti-inflammatory drugs (NSAIDs) are caused by the inhibition of prostaglandin E(2) (PGE(2)), thromboxane A(2) and prostacyclin (PGI(2)) production. Accumulating evidence suggests that the inhibition of PGE(2) production can cause adverse side-effects of NSAIDs on fluid and blood pressure regulation, such as hypertension and edema formation. Since both cyclooxygenase (COX)-1 and COX-2 isoforms contribute to the production of PGE(2), selective COX-2 inhibitors are not free of these adverse side-effects although they may be less severe. Four subtypes of PGE(2) receptors have been identified. The antipyretic action of blunted PGE(2) production is mediated predominantly by a reduced input to the prostaglandin E receptor 3 (EP(3)) pathway, whereas the analgesic action is mediated predominantly by a reduced input to the EP(1) pathway and perhaps by contributions from the other EP receptors. Accordingly, some of the adverse side-effects might be moderated by combined use of NSAIDs with selective EP(2) or EP(4) agonists that do not block the antipyretic or analgesic actions of NSAIDs that are mediated by reduced activation of EP(1) or EP(3) receptors. Moreover, EP(2) receptor-deficient mice had salt-sensitive hypertension and EP(4) receptor blockade moderated salt and water excretion and both EP(2) and EP(4) agonists had renoprotective effects. This suggests that strategies to maintain activation of EP(2) and EP(4) receptors during NSAID administration may not only reduce adverse effects but might confer additional benefits. In conclusion, enhancing EP(2) and EP(4) receptor activity by administration of selective agonists during the administration of NSAIDs has the potential to permit treating fever, inflammation and pain but with marginal adverse effects on fluid or blood pressure regulation.

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Section: Pharmacological Mechanisms Of Nsaids On Fluid and Blood Prescontrasting

confidence: 76%

Section: Pharmacological Mechanisms Of Nsaids On Fluid and Blood Presmentioning

confidence: 99%

Section: Pharmacological Mechanisms Of Nsaids On Fluid and Blood Presmentioning

confidence: 99%

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Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs

et al. 2011

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“…Inhibition of prostaglandin synthesis by NSAIDs and COX-2 inhibitors can result in fluid retention and other renal-based adverse effects, especially under certain disease conditions in which renal function becomes more dependent on prostaglandins (Curtis et al, 2004). Furosemide-induced natriuresis and diuresis represents a useful model for assessing the impact of PGE 2 suppression on sodium and fluid retention because of the increased renal dependence on COX-2-derived PGE 2 (Nü sing et al, 2005). EP receptors, notably EP4, have been shown to be important for furosemide-induced natriuresis in mice (Nü sing et al, 2005).…”

Section: Ep4 Antagonists For Chronic Arthritis 431mentioning

confidence: 99%

“…Furosemide-induced natriuresis and diuresis represents a useful model for assessing the impact of PGE 2 suppression on sodium and fluid retention because of the increased renal dependence on COX-2-derived PGE 2 (Nü sing et al, 2005). EP receptors, notably EP4, have been shown to be important for furosemide-induced natriuresis in mice (Nü sing et al, 2005). In agreement with this finding, we have demonstrated that antagonism of the receptor by MF498 results in significant antinatriuretic and antidiuretic effects similarly to the COX-2 inhibitor MF-tricyclic.…”

Section: Ep4 Antagonists For Chronic Arthritis 431mentioning

confidence: 99%

MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide], a Selective E Prostanoid Receptor 4 Antagonist, Relieves Joint Inflammation and Pain in Rodent Models of Rheumatoid and Osteoarthritis

Clark¹,

Rowland²,

Denis³

et al. 2008

J Pharmacol Exp Ther

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Previous evidence has implicated E prostanoid receptor 4 (EP4) in mechanical hyperalgesia induced by subplantar inflammation. However, its role in chronic arthritis remains to be further defined because previous attempts have generated two conflicting lines of evidence, with one showing a marked reduction of arthritis induced by a collagen antibody in mice lacking EP4, but not EP1-EP3, and the other showing no impact of EP4 antagonism on arthritis induced by collagen. Here, we assessed the effect of a novel and selective EP4 antagonist MF498 [N-{[4-(5,9-diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide] on inflammation in adjuvant-induced arthritis (AIA), a rat model for rheumatoid arthritis (RA), and joint pain in a guinea pig model of iodoacetate-induced osteoarthritis (OA). In the AIA model, MF498, but not the antagonist for EP1,, inhibited inflammation, with a similar efficacy as a selective cyclooxygenase 2 (COX-2) inhibitor MF-tricyclic. In addition, MF498 was as effective as an nonsteroidal anti-inflammatory drug, diclofenac, or a selective microsomal prostaglandin E synthase-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile], in relieving OA-like pain in guinea pigs. When tested in rat models of gastrointestinal toxicity, the EP4 antagonist was well tolerated, causing no mucosal leakage or erosions. Lastly, we evaluated the renal effect of MF498 in a furosemide-induced diuresis model and demonstrated that the compound displayed a similar renal effect as MF-tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone], reducing furosemideinduced natriuresis by ϳ50%. These results not only suggest that EP4 is the major EP receptor in both RA and OA but also provide a proof of principle to the concept that antagonism of EP4 may be useful for treatment of arthritis.Chronic joint inflammation and pain are the two main symptoms in patients with arthritis, such as OA and RA.Joint inflammation begins with cartilage breakdown in OA, whereas the process affects mainly the synovial membrane in RA (Gardner, 1994). Despite this difference, prostaglandins, primarily those derived from COX-2, are key mediators for inflammation and pain in both types of arthritis. Consequently, inhibition of COX-2 and prostaglandin synthesis by Article, publication date, and citation information can be found at

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Cyclooxygenase Metabolites in the Kidney

Harris

Zhang

2011

Comprehensive Physiology

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In the mammalian kidney, prostaglandins (PGs) are important mediators of physiologic processes, including modulation of vascular tone and salt and water. PGs arise from enzymatic metabolism of free arachidonic acid (AA), which is cleaved from membrane phospholipids by phospholipase A2 activity. The cyclooxygenase (COX) enzyme system is a major pathway for metabolism of AA in the kidney. COX are the enzymes responsible for the initial conversion of AA to PGG2 and subsequently to PGH2, which serves as the precursor for subsequent metabolism by PG and thromboxane synthases. In addition to high levels of expression of the "constitutive" rate-limiting enzyme responsible for prostanoid production, COX-1, the "inducible" isoform of cyclooxygenase, COX-2, is also constitutively expressed in the kidney and is highly regulated in response to alterations in intravascular volume. PGs and thromboxane A2 exert their biological functions predominantly through activation of specific 7-transmembrane G-protein-coupled receptors. COX metabolites have been shown to exert important physiologic functions in maintenance of renal blood flow, mediation of renin release and regulation of sodium excretion. In addition to physiologic regulation of prostanoid production in the kidney, increases in prostanoid production are also seen in a variety of inflammatory renal injuries, and COX metabolites may serve as mediators of inflammatory injury in renal disease.

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Dominant Role of Prostaglandin E2 EP4 Receptor in Furosemide-Induced Salt-Losing Tubulopathy

Cited by 51 publications

References 58 publications

Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs

Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs

MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide], a Selective E Prostanoid Receptor 4 Antagonist, Relieves Joint Inflammation and Pain in Rodent Models of Rheumatoid and Osteoarthritis

Cyclooxygenase Metabolites in the Kidney

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