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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Rys-Sikora, Krystyna E
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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