Identification of specific EP receptors responsible for the hemodynamic effects of PGE<sub>2</sub>

Audoly, Laurent; Tilley, Stephen L.; Goulet, Jennifer L.; Key, Mikelle L.; Nguyen, MyTrang; Stock, Jeffrey L.; McNeish, John D.; Koller, Beverly H.; Coffman, Thomas M.

doi:10.1152/ajpheart.1999.277.3.h924

Cited by 73 publications

(83 citation statements)

References 26 publications

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“…28,38,39 Deletion of either EP 2 or EP 4 significantly attenuates the vasodepressor response induced by PGE 2 . 40 Mice lacking EP 2 develop salt-sensitive hypertension. 41,42 Recently, activation of EP 4 receptors was reported to mediate endotheliumdependent stimulation of endothelial NO synthase activity via dephosphorylation at Thr495.…”

Section: Discussionmentioning

confidence: 99%

Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E ₂ Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

et al. 2008

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Abstract-Prostaglandin (PG) E 2 has an established role in the regulation of vascular tone and reactivity. The present study examined the role and mechanism of microsomal PG synthase-1 (mPGES-1) in vascular response to angiotensin II (Ang II) infusion. A 7-day Ang II infusion at 0.35 mg/kg per day via osmotic minipump had no obvious effect on mean arterial blood pressure in mPGES-1 ϩ/ϩ mice but induced a marked hypertensive response in mPGES-1 Ϫ/Ϫ mice, associated with a parallel increase in urinary 8-isoprostane excretion and aortic NADPH oxidase activity and mRNA expression of p47 phox , gp91 phox , and Nox1. The hypertension in mPGES-1 Ϫ/Ϫ mice was completely prevented by Tempol treatment and was fully restored on termination of the antioxidant. Apocynin induced a similar blood pressure-lowering effect as Tempol. The Ang II infusion induced mRNA expression of mPGES-1, as well as mPGES-2 and cytosolic PGE synthase in the aortas as assessed by real-time RT-PCR. Immunohistochemistry revealed remarkably enhanced immunoreactivity of mPGES-1 mostly in vascular smooth muscle cells. In cultured vascular smooth muscle cells, Ang II exerted a direct stimulatory effect on reactive oxygen species production, NADPH oxidase activity, and expression of p47 phox , gp91 phox , and Nox1 that were all inhibited by PGE 2 . The Ϫ/Ϫ mice also exhibited enhanced renal hemodynamic response to acute Ang II infusion at 150 nmol/kg per minute via a jugular vein over a period of 40 minutes. These results suggest that mPGES-1-derived PGE 2 buffers Ang II-induced vasoconstriction via inhibition of NADPH oxidase-dependent reactive oxygen species production. Key Words: mPGES-1 Ⅲ angiotensin II Ⅲ mean arterial pressure Ⅲ oxidative stress Ⅲ NADPH oxidase P rostaglandin (PG) E 2 is a major product of arachidonic acid metabolism, being implicated in pain and inflammatory responses, as well as in the regulation of various physiological functions. 1 The biosynthesis of PGE 2 requires 3 sequential steps of the cyclooxygenase pathway: the release of arachidonic acid from membrane glycerophospholipids by phospholipase A 2 , conversion of arachidonic acid to the unstable intermediate PGH 2 by cyclooxygenase-1 or cyclooxygenase-2, and isomerization of PGH 2 to PGE 2 by PGE synthase (PGES). 2,3 To date, Ն3 major forms of PGES have been cloned and characterized: membrane-associated PGES (mPGES)-1, mPGES-2, and cytosolic PGES (cPGES). 3 Several recent studies using mPGES-1-deficient mice demonstrate a major role of mPGES-1 in pain and inflammatory responses. 4,5 The cardiovascular consequences associated with cyclooxygenase-2 inhibitors 6 -9 have stimulated the interest regarding mPGES-1 as a potential target for the next generation of anti-inflammatory drugs. 10

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Section: Discussionmentioning

confidence: 99%

Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E ₂ Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

et al. 2008

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“…It is a potent vasodilator in both the peripheral (45) and renal vasculature (46). Moreover, PGE 2 has potent natriuretic effects in the kidney through direct epithelial effects on salt and water transport and as a consequence of its hemodynamic actions to increase renal blood flow (3,8).…”

Section: Discussionmentioning

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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“…PGE2 has both vasodilating and vasoconstricting properties, and EP1 and EP3 may mediate the vasoconstricting action (25,26). Treatment of rats with ONO-8713 resulted in transient and slight reduction in BP at 4 wk as compared with untreated or aspirin-treated rats (P Ͻ 0.05; Table 1).…”

Section: Characteristics Of Experimental Animalsmentioning

confidence: 98%

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

Makino¹,

Tanaka²,

Mukoyama³

et al. 2002

Journal of the American Society of Nephrology

107

100

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Abstract. Local production of prostaglandins (PGs) in the kidney is increased in clinical and experimental diabetic nephropathy, but the role of PGs in the pathogenesis and progression of diabetic nephropathy has remained unclear. It is here shown that an orally active antagonist selective for the PGE receptor EP1 subtype potently prevents the progression of nephropathy in streptozotocin-induced diabetic rats. The effects are shown by ameliorated renal and glomerular hypertrophy, decreased mesangial expansion, inhibited transcriptional activation of transforming growth factor-␤ (TGF-␤) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-␤ and fibronectin upregulation in mesangial cells cultured under high-glucose conditions. These data indicate that the PGE2-EP1 system plays a crucial role in the development of diabetic renal injury in rats. It is further shown that both the EP1 antagonist and aspirin, a nonselective PG synthase inhibitor, markedly attenuate mesangial expansion, whereas only the EP1 antagonist inhibits glomerular hypertrophy and proteinuria, which suggests that these changes are caused by different mechanisms. This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease.

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Identification of specific EP receptors responsible for the hemodynamic effects of PGE₂

Cited by 73 publications

References 26 publications

Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E ₂ Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E ₂ Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

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Identification of specific EP receptors responsible for the hemodynamic effects of PGE2

Cited by 73 publications

References 26 publications

Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E 2 Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E 2 Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

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Identification of specific EP receptors responsible for the hemodynamic effects of PGE₂

Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E ₂ Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E ₂ Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress