This PPG was started in September, 1982. The central theme is "the study ofthe role of vasoactive systems (autocrine, juxtacrine, paracrine and endocrine) in the regulation of renal function and blood pressure (BP) and mediation of end organ damage (EOD)". The general hypothesis to be tested is that there is a balance between systems that promote water and sodium retention, hypertension and EOD, including Angiotensin II (Ang II), prostanoids, reactive oxygen species and inflammation, and systems that antagonize these effects like Ac-SDKP, activation of the Ang II type 2 receptor (AT2), kinins, NO, PGE2/EP4, and the newly discovered cross-talk between the connecting tubule and the afferent arteriole (CTGF) which may participate in both natriuresis and renal damage. Alterations of this balance in favor of the former are responsible for retention of water and sodium and development of hypertension and EOD, 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 in hypertension in rats and various transgenic and gene knockout mice. We will mainly use Dahl salt-sensitive rats (Dahl SS) and Ang ll-induced hypertensive rats as models. In Project I, using Dahl SS rats, we will study whether N-acetyl-seryl-aspartyl-lysyl-proline protects against EOD by decreasing adaptive immunity. In Project II we will study whether expression of cyclooxygenase-2 and generation of PGE2 via the EP4 receptor protects against EOD in Ang ll-induced hypertension. In Project III, using Dahl SS rats, we will study whether CTGF causes glomerular damage via afferent arterole dilatation and increases in capillary glomerular pressure. In Project IV, using Dahl SS rats, we will study whether a decrease in the renal thick ascending limb AT2-signaling participates in the pathogenesis of hypertension. Four cores. Administrative (A), Analytical and Morphological (B), Mutant Mouse (C), and Biostatistics (D) will support the scientific efforts of the investigators. Te PPG provides integration of our efforts, collaboration, sharing of ideas and expertise, thus accelerating acquisition of knowledge on the causes of hypertension and EOD.

Public Health Relevance

In the US population hypertension is a major risk for cardiovascular and renal morbility and mortality. Understanding the role of autocrine, paracrine and endocrine systems in the regulation of renal function and BP, in the pathogenesis of EOD is of great relevance since it could lead to better treatment of hypertension, its complications, and reduce morbility and mortality caused by this silent killer.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL028982-32
Application #
8611936
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
OH, Youngsuk
Project Start
1982-09-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
32
Fiscal Year
2014
Total Cost
$2,225,087
Indirect Cost
$706,256
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Ramseyer, Vanesa D; Gonzalez-Vicente, Agustin; Carretero, Oscar A et al. (2015) Angiotensin II-induced hypertension blunts thick ascending limb NO production by reducing NO synthase 3 expression and enhancing threonine 495 phosphorylation. Am J Physiol Renal Physiol 308:F149-56
Kassem, Kamal M; Clevenger, Margarette H; Szandzik, David L et al. (2014) PGE2 reduces MMP-14 and increases plasminogen activator inhibitor-1 in cardiac fibroblasts. Prostaglandins Other Lipid Mediat 113-115:62-8
Cabral, Pablo D; Hong, Nancy J; Hye Khan, Md Abdul et al. (2014) Fructose stimulates Na/H exchange activity and sensitizes the proximal tubule to angiotensin II. Hypertension 63:e68-73
Ren, YiLin; D'Ambrosio, Martin A; Garvin, Jeffrey L et al. (2014) Mechanism of impaired afferent arteriole myogenic response in Dahl salt-sensitive rats: role of 20-HETE. Am J Physiol Renal Physiol 307:F533-8
Gonzalez, German E; Rhaleb, Nour-Eddine; Nakagawa, Pablo et al. (2014) N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen cross-linking and inflammation in angiotensin II-induced hypertensive rats. Clin Sci (Lond) 126:85-94
Xu, Jiang; Sun, Ying; Carretero, Oscar A et al. (2014) Effects of cardiac overexpression of the angiotensin II type 2 receptor on remodeling and dysfunction in mice post-myocardial infarction. Hypertension 63:1251-9
Peng, Hongmei; Xu, Jiang; Yang, Xiao-Ping et al. (2014) Thymosin-?4 prevents cardiac rupture and improves cardiac function in mice with myocardial infarction. Am J Physiol Heart Circ Physiol 307:H741-51
Ren, YiLin; D'Ambrosio, Martin A; Garvin, Jeffrey L et al. (2014) Aldosterone sensitizes connecting tubule glomerular feedback via the aldosterone receptor GPR30. Am J Physiol Renal Physiol 307:F427-34
Ren, Yilin; D'Ambrosio, Martin A; Garvin, Jeffrey L et al. (2013) Prostaglandin E2 mediates connecting tubule glomerular feedback. Hypertension 62:1123-8
Rhaleb, Nour-Eddine; Pokharel, Saraswati; Sharma, Umesh C et al. (2013) N-acetyl-Ser-Asp-Lys-Pro inhibits interleukin-1*-mediated matrix metalloproteinase activation in cardiac fibroblasts. Pflugers Arch 465:1487-95

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