Evidence that separate PGE2 receptors modulate water and sodium transport in rabbit cortical collecting duct

Hébert, Richard; Jacobson, Howard; Fredin, D.; Breyer, Matthew D.

doi:10.1152/ajprenal.1993.265.5.f643

Cited by 94 publications

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“…Only in the presence of vasopressin did PGE 2 greatly affect the transport properties of the collecting duct. 26 In a rat study of straight PT, Garvin 49 demonstrated a 20% response in fluid transport with angiotensin II, but to the best of our knowledge there are no other studies looking at hormonally stimulated water transport in the mouse PT. Interestingly, the minimal responses in the PT may be due to shifting of transport between paracellular and transcellular pathways, so that by altering aquaporin-1 mediated transcellular transport in response to angiotensin II or PGE 2 , paracellular transport is reduced, and overall balance is maintained.…”

Section: Discussionmentioning

confidence: 99%

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Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors

Nasrallah

Hassouneh

Zimpelmann

et al. 2015

Laboratory Investigation

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Renal prostaglandin (PG) E 2 regulates salt and water transport, and affects disease processes via EP 1-4 receptors, but its role in the proximal tubule (PT) is unknown. Our study investigates the effects of PGE 2 on mouse PT fluid reabsorption, and its role in growth, sodium transporter expression, fibrosis, and oxidative stress in a mouse PT cell line (MCT). To determine which PGE 2 EP receptors are expressed in MCT, qPCR for EP 1-4 was performed on cells stimulated for 24 h with PGE 2 or transforming growth factor beta (TGFβ), a known mediator of PT injury in kidney disease. EP 1 and EP 4 were detected in MCT, but EP 2 and EP 3 are not expressed. EP 1 was increased by PGE 2 and TGFβ, but EP 4 was unchanged. To confirm the involvement of EP 1 and EP 4 , sulprostone (SLP, EP 1/3 agonist), ONO8711 (EP 1 antagonist), and EP 1 and EP 4 siRNA were used. We first show that PGE 2 , SLP, and TGFβ reduced H 3 -thymidine and H 3 -leucine incorporation. The effects on cell-cycle regulators were examined by western blot. PGE 2 increased p27 via EP 1 and EP 4 , but TGFβ increased p21; PGE 2 -induced p27 was attenuated by TGFβ. PGE 2 and SLP reduced cyclinE, while TGFβ increased cyclinD1, an effect attenuated by PGE 2 administration. Na-K-ATPase α1 (NaK) was increased by PGE 2 via EP 1 and EP 4 . TGFβ had no effect on NaK. Additionally, PGE 2 and TGFβ increased fibronectin levels, reaching 12-fold upon co-stimulation. EP 1 siRNA abrogated PGE 2 -fibronectin. PGE 2 also increased ROS generation, and ONO-8711 blocked PGE 2 -ROS. Finally, PGE 2 significantly increased fluid reabsorption by 31 and 46% in isolated perfused mouse PT from C57BL/6 and FVB mice, respectively, and this was attenuated in FVB-EP 1 null mice. Altogether PGE 2 acting on EP 1 and EP 4 receptors may prove to be important mediators of PT injury, and salt and water transport. Prostaglandin (PG) E 2 is a major product of cyclooxygenase activity in the kidney. It has a substantial role in maintaining hemodynamics, salt and water homeostasis, and affects growth, inflammation, oxidative stress, and fibrotic responses (reviewed in refs. 1-3 ). Four EP receptors (EP 1-4 ) mediate the signalling responses to PGE 2 , by altering intracellular cAMP and/or Ca 2+ levels. Renal cells often simultaneously express multiple EP receptors, and their relative levels determine the cell's response. Although the contribution of the proximal tubule (PT) to overall renal prostaglandin synthesis is minimal, the role of PGE 2 in PT transport function has been considered. For instance, PGE 2 stimulates cAMP and activates protein kinase A, and in turn regulates basolateral organic anion uptake. 4,5 In contrast, long-term exposure to PGE 2 inhibits its excretion by decreasing the levels of basolateral organic anion transporters that are responsible for PGE 2 uptake in rat renal PT cells. 6 The underlying regulatory pathways are not completely understood, but short-term vs long-term exposure to PGE 2 has opposite effects on the overall cell response. PGE 2 also reduces phosphate transpo...

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Section: Discussionmentioning

confidence: 99%

“…25,26 Microdissected tubules (described above) were transferred to a thermostatically controlled chamber of 1 cm 3 volume and cannulated using concentric micropipettes. Bath solution was continuously exchanged at 0.5 ml/min by infusion pump (Harvard Apparatus, Holliston, MA, USA) and was maintained at 37°C.…”

Section: Measurement Of Net Fluid Reabsorption (Jv)mentioning

confidence: 99%

Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors

Nasrallah

Hassouneh

Zimpelmann

et al. 2015

Laboratory Investigation

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“…PGE2 is synthesized and released in the collecting duct, which expresses all four EP receptors (9)(10)(11). Interestingly, at sites where EP1-4 are present, including the collecting duct, PGE2 is known to have opposing effects; e.g., PGE2 has been shown both to increase water permeability and to decrease the effect of high levels of VP in the cortical collecting duct (12).…”

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confidence: 99%

Vasopressin-independent targeting of aquaporin-2 by selective E-prostanoid receptor agonists alleviates nephrogenic diabetes insipidus

Olesen

Rützler

Moeller

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

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In the kidney, the actions of vasopressin on its type-2 receptor (V2R) induce increased water reabsorption alongside polyphosphorylation and membrane targeting of the water channel aquaporin-2 (AQP2). Loss-of-function mutations in the V2R cause Xlinked nephrogenic diabetes insipidus. Treatment of this condition would require bypassing the V2R to increase AQP2 membrane targeting, but currently no specific pharmacological therapy is available. The present study examined specific E-prostanoid receptors for this purpose. In vitro, prostaglandin E2 (PGE2) and selective agonists for the E-prostanoid receptors EP2 (butaprost) or EP4 (CAY10580) all increased trafficking and ser-264 phosphorylation of AQP2 in Madin-Darby canine kidney cells. Only PGE2 and butaprost increased cAMP and ser-269 phosphorylation of AQP2. Ex vivo, PGE2, butaprost, or CAY10580 increased AQP2 phosphorylation in isolated cortical tubules, whereas PGE2 and butaprost selectively increased AQP2 membrane accumulation in kidney slices. In vivo, a V2R antagonist caused a severe urinary concentrating defect in rats, which was greatly alleviated by treatment with butaprost. In conclusion, EP2 and EP4 agonists increase AQP2 phosphorylation and trafficking, likely through different signaling pathways. Furthermore, EP2 selective agonists can partially compensate for a nonfunctional V2R, providing a rationale for new treatment strategies for hereditary nephrogenic diabetes insipidus.T he anti-diuretic hormone vasopressin (VP) controls wholebody water balance mainly by regulating the water permeability of the kidney collecting duct. VP binds to the Gs-proteincoupled VP type 2 receptor (V2R) in collecting duct principal cells, stimulating the accumulation of aquaporin-2 (AQP2) in the apical plasma membrane (1). This process increases the water permeability of the epithelium, allowing water to be reabsorbed from the collecting-duct lumen and increasing the concentration of the urine. The intracellular signaling cascades of VP in the collecting duct involve increased cAMP and protein kinasedependent phosphorylation of AQP2 at ser-256, ser-264, and ser-269. The ser-256 and ser-269 sites appear to be essential for apical membrane accumulation of AQP2 (2). Although VP's role is well characterized, there is evidence that alternative mechanisms may also regulate water permeability. For example, functional studies on collecting ducts have shown an EC 50 of 10 −11 M for VP-induced increases in water permeability and a requirement of 10 −8 M for maximal effect (3). Water restriction does not increase plasma VP to these levels (4-6). This leaves room for additional mechanisms to be involved in modulating collecting-duct water permeability, supported by evidence that the urinary concentrating ability of the kidney can increase in the presence of a V2R antagonist during water restriction (7).Prostanoids are a family of arachidonic acid derivatives produced in most cell types. The biological actions of one class of prostanoids, prostaglandin E2 (PGE2), are diverse. This may...

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“…With respect to PGE 2 s ability to modulate urine concentrating mechanisms, previous studies focused on the EP 3 receptor subtype as it is highly expressed in the principal cells of the collecting duct. Signaling through this subtype involves a G i -coupled mechanism which limits AVP-mediated cAMP production required for water transport (15). More recent studies have suggested that the EP 3 subtype carries out such putative diuretic effects by activating Rho kinase and F-actin polymerization (31).…”

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confidence: 99%

Urine concentrating defect in prostaglandin EP₁-deficient mice

Kennedy¹,

Xiong²,

Rahal³

et al. 2007

American Journal of Physiology-Renal Physiology

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We investigated the role of the prostaglandin E2 (PGE2) EP1 receptor in modulating urine concentration as it is expressed along the renal collecting duct where argininevasopressin (AVP) exerts its anti-diuretic activity, and in the paraventricular and supraoptic nuclei of the hypothalamus where AVP is synthesized. The urine osmolality of EP 1-null mice (EP1 Ϫ/Ϫ ) failed to match levels achieved by wild-type (WT) counterparts upon water deprivation (WD) for 24 h. This difference was reflected by higher plasma osmolality in WD EP 1 Ϫ/Ϫ mice. Along the collecting duct, the induction and subapical to plasma membrane translocation of the aquaporin-2 water channel in WD EP Ϫ/Ϫ mice. When mice were water loaded to suppress endogenous AVP production, urine osmolalities increased equally for WT and EP 1 Ϫ/Ϫ mice. These data suggest that PGE 2 modulates urine concentration by acting at EP 1 receptors, not in the collecting duct, but within the hypothalamus to promote AVP synthesis in response to acute WD. vasopressin; urine concentration; prostaglandin E 2; EP1 receptor URINE CONCENTRATION IS A HIGHLY regulated process requiring the coordinated actions of a number of hormones at several tissue locales (2). The body responds to acute volume depletion, infection, or hyperosmolality by stimulating the production of antidiuretic hormone, arginine-vasopressin (AVP), within the hypothalamic paraventricular (PVN) and supraoptic (SON) neurons. AVP is then processed, stored, and secreted into the venous flow by the posterior pituitary to interact with renal V 2 receptors located in the principal cells of the collecting duct to promote aquaporin-2 (AQP2)-dependent water reabsorption (25). Many of these steps are subject to modulation by endocrine factors such as ANG II, catecholamines, as well as certain metabolites of the cyclooxygenase (COX) pathway, the prostaglandins (PGs) (2). Accordingly, renal prostaglandin E 2 (PGE 2 ) antagonizes the actions of AVP since NSAIDs transiently enhance urine concentration (1). Direct evidence for the underlying mechanism was provided by who demonstrated that PGE 2 attenuates vasopressin-stimulated osmotic water reabsorption in isolated microperfused rabbit collecting ducts. Subsequent cell culture studies showed that PGE 2 counteracts AVP action by enhancing AQP2 endocytotic uptake from the apical plasma membrane (33). On the other hand, recent studies showed that inhibition of COX by indomethacin reduced renal AQP2 expression in rats, implying that PGs may actually help maintain AQP2 levels (20).In addition to the well-known renal effects of PGs on urine concentration, other evidence suggests that COX-derived products could influence this process by acting at central locales. Early studies showed that AVP release was stimulated by PGE 2 in the rat neurohypophysis (32). Ishikawa et al. (17) showed a reduced release of AVP in response to either hyperosmotic exposure or ANG II in guinea pig hypothalamoneurohypophyseal cultures following treatment with indomethacin. Finally, an intracerebroventri...

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Evidence that separate PGE2 receptors modulate water and sodium transport in rabbit cortical collecting duct

Cited by 94 publications

References 0 publications

Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors

Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors

Vasopressin-independent targeting of aquaporin-2 by selective E-prostanoid receptor agonists alleviates nephrogenic diabetes insipidus

Urine concentrating defect in prostaglandin EP₁-deficient mice

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Evidence that separate PGE2 receptors modulate water and sodium transport in rabbit cortical collecting duct

Cited by 94 publications

References 0 publications

Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors

Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors

Vasopressin-independent targeting of aquaporin-2 by selective E-prostanoid receptor agonists alleviates nephrogenic diabetes insipidus

Urine concentrating defect in prostaglandin EP1-deficient mice

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Urine concentrating defect in prostaglandin EP₁-deficient mice