Prostaglandin E2 inhibits renal collecting duct Na+ absorption by activating the EP1 receptor.

Guan, Youfei; Zhang, Ya-Hua; Breyer, Richard M.; Fowler, Beth C.; Davis, Linda S.; Hébert, Richard; Breyer, Matthew D.

doi:10.1172/jci2872

Cited by 130 publications

(107 citation statements)

References 52 publications

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“…9 As in the case of hypertensive renal injury, local PGE 2 production in the kidney is increased in diabetic nephropathy. 37,38 Furthermore, treatment by EP 1 A ameliorates not only renal injury in genetically hypertensive rats as shown here but also diabetic nephropathy induced by streptozotocin. 24 Therefore, it may be conceivable that relative overactivation of EP 1 and functional impairment of EP 4 are common mediators of renal injuries caused both by hypertension and diabetes.…”

Section: Perspectivessupporting

confidence: 60%

Role of Prostaglandin E Receptor EP ₁ Subtype in the Development of Renal Injury in Genetically Hypertensive Rats

et al. 2003

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Abstract-One of the major causes of end-stage renal diseases is hypertensive renal disease, in which enhanced renal prostaglandin (PG) E 2 production has been shown. PGE 2 , a major arachidonic acid metabolite produced in the kidney, acts on 4 receptor subtypes, EP 1 through EP 4 , but the pathophysiological importance of the PGE 2 /EP subtypes in the development of hypertensive renal injury remains to be elucidated. In this study, we investigated whether an orally active EP 1 -selective antagonist (EP 1 A) prevents the progression of renal damage in stroke-prone spontaneously hypertensive rats (SHRSP), a model of human malignant hypertension. Ten-week-old SHRSP, with established hypertension but with minimal renal damage, were given EP 1 A or vehicle for 5 weeks. After the treatment period, vehicle-treated SHRSP showed prominent proliferative lesions in arterioles, characterized by decreased ␣-smooth muscle actin expression in multilayered vascular smooth muscle cells. Upregulation of transforming growth factor-␤ expression and tubulointerstitial fibrosis were also observed in vehicle-treated SHRSP. All these changes were dramatically attenuated in EP 1 A-treated SHRSP. Moreover, EP 1 A treatment significantly inhibited both increase in urinary protein excretion and decrease in creatinine clearance but had little effect on systemic blood pressure.

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Section: Perspectivessupporting

confidence: 60%

Role of Prostaglandin E Receptor EP ₁ Subtype in the Development of Renal Injury in Genetically Hypertensive Rats

et al. 2003

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“…Nonetheless, several studies have evalu-ated regional expression of mPGES1 in the kidney by in situ hybridization and immunocytochemistry (5,(17)(18)(19). There is a general agreement among these studies that mPGES1 is expressed in the distal nephron from the connecting tubule through the cortical and medullary collecting duct (5,(17)(18)(19).…”

mentioning

confidence: 99%

“…PGE 2 also modulates renal sodium and water excretion (1,4). Studies in isolated perfused nephron segments suggest that PGE 2 acting through E-prostanoid (EP) receptors such as EP1 may directly stimulate solute flux in renal epithelia (5). PGE 2 may also influence water permeability in the distal nephron by opposing the actions of the stimulated G-protein-linked vasopressin receptor (4).…”

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confidence: 99%

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

François

Facemire

Kumar

et al. 2007

Journal of the American Society of Nephrology

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Prostaglandin E 2 (PGE 2 ) is one of the most ubiquitous prostanoids in the kidney, where it may influence a wide range of physiologic functions. PGE 2 is generated through enzymatic metabolism of prostanoid endoperoxides by specific PGE synthases (PGES). Several putative PGES have been identified and cloned, including the membrane-associated, inducible microsomal PGES1 (mPGES1), which is expressed in the kidney. To evaluate the physiologic role of mPGES1 in the kidney, mice with targeted disruption of mPges1 gene were studied, with a focus on responses where PGE 2 has been implicated, including urinary concentration, regulation of blood pressure, and response to a loop diuretic. The absence of mPGES1 was associated with a 50% decrease in basal excretion of PGE 2 in urine (P < 0.001). In female but not male mPGES1-deficient mice, there was a reciprocal increase in basal excretion of other prostanoids. Nonetheless, urinary osmolalities were similar in mPges1 ؉/؉ and mPges1 ؊/؊ mice at baseline and after 12 h of water deprivation. Likewise, there were no differences in blood pressure between mPGES1-deficient and wild-type mice on control or high-or low-salt diets. The furosemide-induced increase in urinary PGE 2 excretion that was seen in wild-type mice was attenuated in mPGES1-deficient mice. However, furosemide-associated diuresis was reduced only in male, not female, mPGES1-deficient mice. Stimulation of renin by furosemide was not affected by mPGES1 deficiency. These data suggest that mPGES1 contributes to basal synthesis of PGE 2 , but there are other pathways that lead to renal PGE 2 synthesis. Moreover, there are significant gender differences in physiologic contributions of mPGES1 to control kidney function.

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“…Both EP2 and EP4 can signal via increased cAMP (8). 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.

114

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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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Prostaglandin E2 inhibits renal collecting duct Na+ absorption by activating the EP1 receptor.

Cited by 130 publications

References 52 publications

Role of Prostaglandin E Receptor EP ₁ Subtype in the Development of Renal Injury in Genetically Hypertensive Rats

Role of Prostaglandin E Receptor EP ₁ Subtype in the Development of Renal Injury in Genetically Hypertensive Rats

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

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

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Prostaglandin E2 inhibits renal collecting duct Na+ absorption by activating the EP1 receptor.

Cited by 130 publications

References 52 publications

Role of Prostaglandin E Receptor EP 1 Subtype in the Development of Renal Injury in Genetically Hypertensive Rats

Role of Prostaglandin E Receptor EP 1 Subtype in the Development of Renal Injury in Genetically Hypertensive Rats

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

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

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Role of Prostaglandin E Receptor EP ₁ Subtype in the Development of Renal Injury in Genetically Hypertensive Rats

Role of Prostaglandin E Receptor EP ₁ Subtype in the Development of Renal Injury in Genetically Hypertensive Rats