Abstract

Prostaglandin E2 (PGE2) regulates blood pressure, where it can exert either vasopressor or vasodepressor effects. These physiologically opposing effects can be explained in part by the existence of four PGE2 receptors, designated the E-Prostanoid (EP) receptors EP1 through EP4. The EP1 and EP3 receptors primarily mediate the pressor response, while the EP2 and EP4 receptors mediate the depressor response. We will investigate the role of the pressor effects of PGE2 utilizing EP1 and EP3 null mouse models. We will determine the mechanism by which angiotensin II interacts with EP1 activation. We will further investigate the mechanism of action of the EP3 receptor, which appears to have has quite distinct properties and mechanism of pressor action compared to the EP1 receptor. We hypothesize that the two receptors act in distinct manners on disparate targets and may synergize to produce the pressor effect of PGE2. Because the EP1 receptor has been demonstrated to mediate some of the pressor effects of angiotensin II and the renin-angiotensin-system, we hypothesize that EP1 may mediate renin-angiotensin-system evoked effects on renal fibrosis and chronic kidney disease. To investigate these related hypotheses, we will undertake the following three Specific Aims:
Specific aim 1. To determine the molecular mechanism of EP1 receptor pressor effects.
Specific aim 2 : To determine the molecular mechanism of EP3 receptor pressor effects.
Specific aim 3 : To determine whether EP1 or EP3 receptor blockade will prevent or attenuate the progression of chronic kidney disease.

Public Health Relevance

This project will assess the mechanism of action of two PGE2 receptors and their contribution to elevated blood pressure in the development of renal fibrosis. In vitro studies will focus on the downstream receptor signal transduction of AT1 angiotensin receptor and PGE2 EP receptors to investigate evidence of receptor synergy. Studies will include mouse models of diabetic nephropathy, 5/6 nephrectomy and angiotensin induced hypertension to examine potential mechanisms of renal damage.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037097-24
Application #
7687539
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
1985-08-01
Project End
2012-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
24
Fiscal Year
2009
Total Cost
$326,188
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212

  Publications

Robb, Calum T; McSorley, Henry J; Lee, Jinju et al. (2018) Prostaglandin E2 stimulates adaptive IL-22 production and promotes allergic contact dermatitis. J Allergy Clin Immunol 141:152-162
Kong, Deping; Li, Juanjuan; Shen, Yujun et al. (2017) Niacin Promotes Cardiac Healing after Myocardial Infarction through Activation of the Myeloid Prostaglandin D2 Receptor Subtype 1. J Pharmacol Exp Ther 360:435-444
Duffin, Rodger; O'Connor, Richard A; Crittenden, Siobhan et al. (2016) Prostaglandin E? constrains systemic inflammation through an innate lymphoid cell-IL-22 axis. Science 351:1333-8
Kraemer, Maria P; Choi, Hyehun; Reese, Jeff et al. (2016) Regulation of arterial reactivity by concurrent signaling through the E-prostanoid receptor 3 and angiotensin receptor 1. Vascul Pharmacol 84:47-54
Kong, Deping; Shen, Yujun; Liu, Guizhu et al. (2016) PKA regulatory II? subunit is essential for PGD2-mediated resolution of inflammation. J Exp Med 213:2209-26
Ceddia, Ryan P; Lee, DaeKee; Maulis, Matthew F et al. (2016) The PGE2 EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice. Endocrinology 157:220-32
Oishi, Yo; Yoshida, Kyoko; Scammell, Thomas E et al. (2015) The roles of prostaglandin E2 and D2 in lipopolysaccharide-mediated changes in sleep. Brain Behav Immun 47:172-7
Hoggatt, Jonathan; Mohammad, Khalid S; Singh, Pratibha et al. (2013) Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature 495:365-9
Natarajan, Chandramohan; Hata, Aaron N; Hamm, Heidi E et al. (2013) Extracellular loop II modulates GTP sensitivity of the prostaglandin EP3 receptor. Mol Pharmacol 83:206-16
Downey, Jason D; Saleh, Sam A; Bridges, Thomas M et al. (2013) Development of an in vivo active, dual EP1 and EP3 selective antagonist based on a novel acyl sulfonamide bioisostere. Bioorg Med Chem Lett 23:37-41

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