Research Article| Volume 77, ISSUE 1, P15-20, July 2007

Association between prostaglandin E2 receptor gene and essential hypertension



      Essential hypertension (EH) is a complex multifactorial polygenic disorder that is thought to result from an interaction between an individual's genetic makeup and various environmental factors. In the kidney, prostaglandins (PGs) are important mediators of vascular tone and salt and water homeostasis, and are involved in the mediation and/or modulation of hormonal action. In previous studies, mice deficient in the prostaglandin E2 (PGE2) EP2 receptor had resting systolic blood pressure (BP) that was significantly lower than that of wild-type controls. The BP of those mice increased when they were put on a high-salt diet, suggesting that the EP2 receptor is involved in sodium handling by the kidney. In the present study, we investigated the association between EH and nucleotide polymorphisms in the gene encoding the prostaglandin E2 receptor subtype EP2 (PTGER2).


      We selected three single-nucleotide polymorphisms (SNP) in the human PTGER2 gene (rs1254601, rs2075797, and rs17197), and we performed a genetic association study of 266 EH patients and 253 age-matched normotensive (NT) controls.


      There was no significant difference in overall distribution of genotypes or alleles of any of the SNP between the EH and NT groups. However, among men, the A/A type of the SNP rs17197 (rs17197, A/G in 3′UTR) was significantly more frequent in EH subjects than in NT subjects (P=0.041).


      The present findings suggest that rs17197 is useful as a genetic marker of EH in men.
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        • Cheng H.F.
        • Wang S.W.
        • Zhang M.Z.
        • et al.
        Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2002; 283: 638-646
        • Bonvalet J.P.
        • Pradelles P.
        • Farman N.
        • et al.
        Segmental synthesis and actions of prostaglandins along the nephron.
        Am. J. Physiol. 1987; 253: 377-387
        • Smith W.L.
        Prostanoid biosynthesis and mechanisms of action.
        Am. J. Physiol. 1992; 263: 181-191
        • Narumiya S.
        • Sugimoto Y.
        • Ushikubi F.
        Prostanoid receptors: structures, properties, and functions.
        Physiol. Rev. 1999; 79: 1193-1226
        • Bastien L.
        • Sawyer N.
        • Grygorczyk R.
        • et al.
        Cloning, functional expression, and characterization of the human prostaglandin E2 receptor EP2 subtype.
        J. Biol. Chem. 1994; 269: 11873-11877
        • Regan J.W.
        • Bailey T.J.
        • Pepperl D.J.
        • et al.
        Cloning of a novel human prostaglandin receptor with characteristics of the pharmacologically defined EP2 subtype.
        Mol. Pharmacol. 1994; 46: 213-220
        • Kennedy C.R.
        • Zhang Y.
        • Brandon S.
        • et al.
        Salt-sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor.
        Nat. Med. 1999; 5: 217-220
        • Volpe M.
        • Alderman M.H.
        • Furberg C.D.
        • et al.
        Beyond hypertension toward guidelines for cardiovascular risk reduction.
        Am. J. Hyperens. 2004; 17: 1068-1074
        • Dominiczak A.F.
        • Negrin D.C.
        • Clark J.S.
        • Brosnan M.J.
        • McBride M.W.
        • Alexander M.Y.
        Genes and hypertension: from gene mapping in experimental models to vascular gene transfer strategies.
        Hypertension. 2000; 35: 164-172
        • Williams G.H.
        Genetic factors associated with volume-sensitive hypertension.
        Mol. Cell. Endocrinol. 2004; 217: 41-44
        • Carlson S.H.
        • Oparil S.
        • Chen Y.-F.
        • Wyss J.M.
        Blood pressure and NaCl-sensitive hypertension are influenced by angiotensin-converting enzyme gene expression in transgenic mice.
        Hypertension. 2002; 39: 214-218
        • Risch N.
        • Merikangas K.
        The future of genetic studies of complex human disease.
        Science. 1996; 273: 1516
        • Nakayama T.
        • Soma M.
        • Mizutani Y.
        • et al.
        A novel missense mutation of exon 3 in the type A human natriuretic peptide receptor gene: possible association with essential hypertension.
        Hypertens. Res. 2002; 25: 395-401
        • Nakayama T.
        • Hironaga T.
        • Ishima H.
        • et al.
        The prostacyclin analogue beraprost sodium prevents development of arterial stiffness in elderly patients with cerebral infarction.
        Prostaglandins Leukot. Essent. Fatty Acids. 2004; 70: 491-494
        • Nakayama T.
        • Soma M.
        • Rahmutula D.
        • et al.
        Association study between a novel single nucleotide polymorphism of the promoter region of the prostacyclin synthase gene and essential hypertension.
        Hypertens. Res. 2002; 25: 65-68
        • Oates J.A.
        • FitzGerald G.A.
        • Branch R.A.
        • et al.
        Clinical implications of prostaglandin and thromboxane A2 formation (1).
        N. Engl. J. Med. 1988; 319: 689-698
        • Smith A.D.
        • Dorrance A.M.
        Arachidonic acid induces augmented vasoconstriction via cyclooxygenase 1 in the aorta from rats fed a high-fat diet.
        Prostaglandins Leukot. Essent. Fatty Acids. 2006; 75: 43-49
        • Alanko J.
        • Jolma P.
        • Koobi P.
        • et al.
        Prostacyclin and thromboxane A2 production in nitric oxide-deficient hypertension in vivo. Effects of high calcium diet and angiotensin receptor blockade.
        Prostaglandins Leukot. Essent. Fatty Acids. 2003; 69: 345-350
        • Lariviere R.
        • Moreau C.
        • Rodrigue M.E.
        • Lebel M.
        Thromboxane blockade reduces blood pressure and progression of renal failure independent of endothelin-1 in uremic rats.
        Prostaglandins Leukot. Essent. Fatty Acids. 2004; 71: 103-109
        • Nakayama T.
        • Soma M.
        • Rahmutula D.
        • Izumi Y.
        • Kanmatsuse K.
        Nonsense mutation of prostacyclin synthase gene in a family.
        Lancet. 1997; 349: 1887-1888
        • Nakayama T.
        • Morrow M.J.D.
        • Oates J.A.
        • et al.
        Splicing mutation of the prostacyclin synthase gene in a family associated with hypertension.
        Biochem. Biophys. Res. Commun. 2002; 297: 1135-1139
        • Lee J.B.
        • Attallah A.A.
        Renal prostaglandins.
        Nephron. 1975; 15: 350-368
        • Negishi M.
        • Sugimoto Y.
        • Ichikawa A.
        Molecular mechanisms of diverse actions of prostanoid receptors.
        Biochim. Biophys. Acta. 1995; 1259: 109-119
        • Breyer M.D.
        • Breyer R.M.
        Prostaglandin E receptors and the kidney.
        Am. J. Physiol. Renal. Physiol. 2000; 279: F12-F23
        • Jensen B.L.
        • Stuvve J.
        • Hanen P.
        • et al.
        Localization of prostaglandin E(2) EP2 and EP4 receptors in the rat kidney.
        Am. J. Physiol. Renal. Physiol. 2001; 280: F1009-F2001
        • Narumiya S.
        Prostanoid receptors and signal transduction.
        Prog. Brain Res. 1996; 113: 231-241
        • Toh H.
        • Ichikawa A.
        • Narumiya S.
        Molecular evolution of receptors for eicosanoids.
        FEBS Lett. 1995; 361: 17-21
        • Hebert R.L.
        • Jacobson H.R.
        • Breyer M.D.
        Prostaglandin E2 inhibits sodium transport in rabbit cortical collecting duct by increasing intracellular calcium.
        J. Clin. Invest. 1991; 87: 1992-1998
        • Hebert R.L.
        • Jacobson H.R.
        • Fredin D.
        • Breyer M.D.
        Evidence that separate PGE2 receptors modulate water and sodium transport in rabbit cortical collecting duct.
        Am. J. Physiol. 1993; 265: F643-F650
      1. L. Audoly, H. Kim, J. Patrick, et al., Mice lacking the prostaglandin E2 Ep1 receptor subtype have hypotension, hyperreninemia and altered responses to angiotensin II, FASEB J 13 (1999) A1549 (Abstr.).

        • Tilley S.L.
        • Audoly L.P.
        • Hicks E.H.
        • et al.
        Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E2 receptor.
        J. Clin. Invest. 1999; : 1539-1545
        • Bayorh M.A.
        • Socci R.R.
        • Eatman D.
        • et al.
        The role of gender in salt-induced hypertension.
        Clin. Exp. Hypertens. 2001; 23: 241-255
        • Jennifer C S.
        • Jennifer M S.
        • David M P.
        • et al.
        Sexual dimorphism in renal production of prostanoids in spontaneously hypertensive rats.
        Hypertension. 2005; 45: 406-411
        • Stapleton P.P.
        • Strong V.E.M.
        • Freeman T.A.
        • et al.
        Gender affects macrophage cytokine and prostaglandin E2 production and PGE2 receptor expression after trauma.
        J. Surg. Res. 2004; 122: 1-7
        • O’Donnell C.J.
        • Lindpaintner K.
        • Larson M.G.
        • et al.
        Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the framingham heart study.
        Circulation. 1998; 97: 1766-1772
        • Nakayama T.
        • Kuroi N.
        • Sano M.
        • et al.
        Mutation of the follicle-stimulating hormone receptor gene 5′-untranslated region associated with female hypertension.
        Hypertension. 2006; 48: 512-518