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 #
2P01HL028982-31A1
Application #
8415168
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
2013-02-15
Budget End
2014-01-31
Support Year
31
Fiscal Year
2013
Total Cost
$2,472,318
Indirect Cost
$784,729
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Gonzalez-Vicente, Agustin; Saikumar, Jagannath H; Massey, Katherine J et al. (2016) Angiotensin II stimulates superoxide production by nitric oxide synthase in thick ascending limbs. Physiol Rep 4:
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
Ren, Yilin; Janic, Branislava; Kutskill, Kristopher et al. (2016) Mechanisms of Connecting Tubule Glomerular Feedback Enhancement by Aldosterone. Am J Physiol Renal Physiol :ajprenal.00076.2016
Gu, Xiaosong; Xu, Jiang; Zhu, Liping et al. (2016) Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor. Circ Heart Fail 9:
Zhu, Liping; Yang, Xiao-Ping; Janic, Branislava et al. (2016) Ac-SDKP suppresses TNF-α-induced ICAM-1 expression in endothelial cells via inhibition of IκB kinase and NF-κB activation. Am J Physiol Heart Circ Physiol 310:H1176-83
Ramseyer, Vanesa Daniela; 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 :ajprenal.00473.2015
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
Worou, Morel E; Liao, Tang-Dong; D'Ambrosio, Martin et al. (2015) Renal protective effect of N-acetyl-seryl-aspartyl-lysyl-proline in dahl salt-sensitive rats. Hypertension 66:816-22
Peng, Hongmei; Sarwar, Zeyd; Yang, Xiao-Ping et al. (2015) Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction. Hypertension 66:582-9
Monzon, Casandra M; Garvin, Jeffrey L (2015) Nitric oxide decreases the permselectivity of the paracellular pathway in thick ascending limbs. Hypertension 65:1245-50

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