Cycloxygenase-2 Is Expressed in Vasculature of Normal and Ischemic Adult Human Kidney and Is Colocalized with Vascular Prostaglandin E2 EP4 Receptors

Therland, Karina; Stubbe, Jane; Thiesson, Helle C.; Ottosen, Peter D.; Walter, Steen; Sørensen, Grith Lykke; Skøtt, Ole; Jensen, Boye L.

doi:10.1097/01.asn.0000124673.79934.24

Cited by 63 publications

(54 citation statements)

References 38 publications

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“…18 -22 The data presented here show that very modest changes in JG interstitial fluid osmolality may have a COX-2-dependent effect on renin release directly at the level of the JG cell and independent of the macula densa. This notion of JG cell prostaglandin production and efflux is supported by the present demonstration of COX-2 and PGT mRNAs encoding PGT and OATP-D in single JG cells and previous data, which show COX-2 and PGT in renal microvessels 23,24 Do variations in interstitial JG osmolality occur in vivo? In the freshwater salamander Amphiuma, the interstitial concentration of chloride can reach levels significantly above isotonic, 5 and mathematical models show that localized variation in interstitial NaCl concentration may occur in the mammalian JG apparatus.…”

Section: Discussionsupporting

confidence: 74%

Hypotonicity-Induced Renin Exocytosis from Juxtaglomerular Cells Requires Aquaporin-1 and Cyclooxygenase-2

Friis

Madsen²,

Svenningsen³

et al. 2009

Journal of the American Society of Nephrology

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The mechanism by which extracellular hypotonicity stimulates release of renin from juxtaglomerular (JG) cells is unknown. We hypothesized that osmotically induced renin release depends on water movement through aquaporin-1 (AQP1) water channels and subsequent prostanoid formation. We recorded membrane capacitance (C m ) by whole-cell patch clamp in single JG cells as an index of exocytosis. Hypotonicity increased C m significantly and enhanced outward current. Indomethacin, PLA 2 inhibition, and an antagonist of prostaglandin transport impaired the C m and current responses to hypotonicity. Hypotonicity also increased exocytosis as determined by a decrease in single JG cell quinacrine fluorescence in an indomethacin-sensitive manner. In single JG cells from COX-2 Ϫ/ Ϫ and AQP1 Ϫ/ Ϫ mice, hypotonicity increased neither C m nor outward current, but 0.1-M PGE 2 increased both in these cells. A reduction in osmolality enhanced cAMP accumulation in JG cells but not in renin-producing As4.1 cells; only the former had detectable AQP1 expression. Inhibition of protein kinase A blocked the hypotonicity-induced C m and current response in JG cells. Taken together, our results show that a 5 to 7% decrease in extracellular tonicity leads to AQP1-mediated water influx in JG cells, PLA 2 /COX-2-mediated prostaglandin-dependent formation of cAMP, and activation of PKA, which promotes exocytosis of renin. Juxtaglomerular (JG) granular cells in the terminal part of the renal afferent glomerular arterioles are the only cells in the organism that synthesize preprorenin, process it to active renin, and store active renin in mature secretory granules. The rate of renin granule exocytosis determines the level of activation of the renin-angiotensin-aldosterone system. Renin secretion from most 1,2 but not all 3,4 in vitro preparations displays a uniquely high sensitivity to changes in extracellular osmolality such that a moderate reduction in the extracellular osmolality leads to rapid increases in renin secretion. The sensing and transduction events for renin release in response to osmotic perturbations are not known. At the glomerular tuft, the extracellular osmolality may vary depending on sodium chloride (NaCl)transport rate by the adjacent macula densa and thick ascending limb cells, which are relatively water impermeable. 5,6 JG cell capacitance (C m ), an index of cell surface area, increased when extracellular osmolality was decreased by 5 to 10% at the single cell level. 7 This observation shows exocytotic release of renin in response to decreases in extracellular osmolality. 7 Introduction of a pipette solution

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Section: Discussionsupporting

confidence: 74%

Hypotonicity-Induced Renin Exocytosis from Juxtaglomerular Cells Requires Aquaporin-1 and Cyclooxygenase-2

Friis

Madsen²,

Svenningsen³

et al. 2009

Journal of the American Society of Nephrology

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“…Butaprost increased ser-256 phosphorylation of AQP2 in cortical tubule suspensions and increased apical membrane accumulation of AQP2 in rat kidney slices, 18 indicating that EP2 is expressed in the CD, which has previously been an issue of some debate. 13,14,16,[18][19][20][21][22][23] This notion was further strengthened by the finding that butaprost was able to decrease polyuria in a rat model of x-linked NDI. Together, EP2 and EP4 are potential candidates for mediating urinary concentration in conditions with absent V2R signaling, but whether they can act alongside VP to increase urine concentration remains unknown.…”

mentioning

confidence: 51%

“…16,18 EP2 has also been localized to mouse CCD cells, 14 the rabbit CCD, 33 and the human connecting tubule, 20 but kidney EP2 localization in mouse, rabbit, and human CDs is not consistently found. 13,14,21,22,33 EP2 is also expressed in renomedullary interstitial cells.…”

Section: Postobstructive Polyuriamentioning

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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“…COX-1 generated prostaglandins cause diuresis (25) and COX-2 generated prostaglandins may have antidiuretic effects, as COX-2 expression in the renal medulla is markedly stimulated by water deprivation (26,27). Moreover, COX-1 is the constitutive form, whereas COX-2 is believed to be the inducible form, although recently the latter has been found to be constitutive in renal vessels (28). In view of their opposing effects, it may be proposed that a balance between COX-1 and COX-2 activities may determine fluid and electrolyte excretion by the kidney.…”

Section: Discussionmentioning

confidence: 99%

Comparative Effects of Indomethacin and Nabumetone on Urine and Electrolyte Output in Conscious Rats

2005

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Abstract. The effects of indomethacin and nabumetone on urine and electrolyte excretion in conscious rats were examined. Male Sprague-Dawley rats were housed individually for a fiveweek duration, consisting of acclimatization, control, experimental, and recovery phases. During the experimental phase, rats were given either indomethacin (1.5 mg ⋅ kg −1 body weight ⋅ day −1 in 0.5 ml saline, n = 10), nabumetone (15 mg ⋅ kg −1 body weight ⋅ day −1 0.5 ml saline, n = 10), or 0.5 ml saline alone (n = 10) for a period of two weeks. Water and food intake, body weight, urine output, and electrolyte excretions were estimated. Data were analyzed using two-way ANOVA. Urine output in the indomethacin-and nabumetone-treated groups was not different from the controls, but was significantly different between the drug-treated groups (P<0.01). Sodium, potassium, calcium, and magnesium excretions were not different between nabumetone-treated and control rats. However, sodium and potassium excretion was significantly lower in rats receiving indomethacin when compared to the control rats. Calcium and magnesium outputs, although did not differ from the controls, nevertheless decreased significantly with indomethacin (P<0.01). It appears that indomethacin and nabumetone when given at maximum human therapeutic doses may affect urine and electrolyte output in conscious rats.

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Cycloxygenase-2 Is Expressed in Vasculature of Normal and Ischemic Adult Human Kidney and Is Colocalized with Vascular Prostaglandin E2 EP4 Receptors

Abstract: Abstract. The study was performed to elucidate the distribution and cellular localization of cyclooxygenase (COX

Cited by 63 publications

References 38 publications

Hypotonicity-Induced Renin Exocytosis from Juxtaglomerular Cells Requires Aquaporin-1 and Cyclooxygenase-2

Hypotonicity-Induced Renin Exocytosis from Juxtaglomerular Cells Requires Aquaporin-1 and Cyclooxygenase-2

Is There a Role for PGE2 in Urinary Concentration?

Comparative Effects of Indomethacin and Nabumetone on Urine and Electrolyte Output in Conscious Rats

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