This PPG was started in September, 1982. The central theme is """"""""the study of the role of vasoactive systems (autocrine, juxtacrine, paracrine and endocrine) in the regulation of renal function and blood pressure (BP) and mediation of target organ damage"""""""". The general hypothesis to be tested is that there is a balance between systems that promote water and sodium retention, hypertension and target organ damage (Ang II, COX-2 products and free radicals), and systems that antagonize these effects (kinins, NO, Ac-SDKP and activation of the Ang II type 2 receptor). Alterations of this balance in favor of the former are responsible for the development of hypertension and target organ damage, while alterations of this balance in favor of the latter have therapeutic effects. We will use molecular, physiological, and pharmacological approaches to study vasoactive systems at the subcellular, cellular, and isolated organ levels and in intact animals in both acute and chronic models, including transgenic mice. In project 1 we will study whether a novel peptide (Ac-SDKP) alters the balance between systems that promote and oppose target organ damage in favor of the latter, thus preventing and regressing this process. In project 2 we will study whether the local effects of Ang II in the heart are antagonized by activation of the AT2 receptor, kinins and NO. In project 3 we will study whether COX-2 via EP1 and EP3 receptors promotes the development of cardiovascular disease and whether this effect is antagonized by the PPAR receptor. In project 4 we will study the regulation of renal microcirculation by the juxtaglomerular apparatus to see whether there is an interplay between vasodepressor autacoids (NO, kinins and vasodilator eicosanoids) and vasopressor systems (Ang II, reactive oxygen species and cP450 vasoconstrictor metabolites). In project 5 we will study whether NO produced by eNOS in the renal tubules alters the water and sodium balance in favor of natriuresis and diuresis, thus opposing hypertensive stimuli. Four core units (Administrative, Analytical and Morphology, Mutant Mouse, Biostatistics) will support and facilitate the scientific efforts of the investigators. Special expertise is centralized in the cores so that resources can be used more efficiently. The Program Project provides integration of our efforts, continuing collaboration and sharing of ideas and expertise; thus it accelerates acquisition of knowledge on the pathogenesis of hypertension and target organ damage.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Barouch, Winifred
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Henry Ford Health System
Internal Medicine/Medicine
Schools of Medicine
United States
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Kumar, Nitin; Liao, Tang-Dong; Romero, Cesar A et al. (2018) Thymosin ?4 Deficiency Exacerbates Renal and Cardiac Injury in Angiotensin-II-Induced Hypertension. Hypertension 71:1133-1142
Bryson, Timothy D; Gu, Xiaosong; Khalil, Remonda M et al. (2018) Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction. J Mol Cell Cardiol 118:1-12
Cerniello, Flavia M; Carretero, Oscar A; Longo Carbajosa, Nadia A et al. (2017) MAS1 Receptor Trafficking Involves ERK1/2 Activation Through a ?-Arrestin2-Dependent Pathway. Hypertension 70:982-989
Ramseyer, Vanesa D; Ortiz, Pablo A; Carretero, Oscar A et al. (2016) Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs. Am J Physiol Renal Physiol 310:F748-F754
González, Germán E; Rhaleb, N-E; D'Ambrosio, Martin A et al. (2016) Cardiac-deleterious role of galectin-3 in chronic angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 311:H1287-H1296
Gu, Xiaosong; Xu, Jiang; Zhu, Liping et al. (2016) Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor. Circ Heart Fail 9:
Kumar, Nitin; Nakagawa, Pablo; Janic, Branislava et al. (2016) The anti-inflammatory peptide Ac-SDKP is released from thymosin-?4 by renal meprin-? and prolyl oligopeptidase. Am J Physiol Renal Physiol 310:F1026-34
Zhu, Liping; Yang, Xiao-Ping; Janic, Branislava et al. (2016) Ac-SDKP suppresses TNF-?-induced ICAM-1 expression in endothelial cells via inhibition of I?B kinase and NF-?B activation. Am J Physiol Heart Circ Physiol 310:H1176-83
Saez, Fara; Hong, Nancy J; Garvin, Jeffrey L (2016) Luminal flow induces NADPH oxidase 4 translocation to the nuclei of thick ascending limbs. Physiol Rep 4:
Cerrato, Bruno D; Carretero, Oscar A; Janic, Brana et al. (2016) Heteromerization Between the Bradykinin B2 Receptor and the Angiotensin-(1-7) Mas Receptor: Functional Consequences. Hypertension 68:1039-48

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