About 30% of the US population is hypertensive, and a large portion is salt-sensitive. Activation of angiotensin II (Ang II) type 1 receptors (ATi) promotes salt retention by stimulating nephron transport and constricting renal vessels, while stimulating type 2 receptors (AT2) promotes salt excretion. ImlDalances favoring the former increase blood pressure (BP), and end organ (damage (EOD). Thick ascending limbs (THALs) reabsorb 25-30% of filtered NaCl through both trans- and paracellular pathways. We and others reported that ATi activation stimulated protein kinase C and O2", both of which usually enhance THAL NaCl absorption. We also showed that stimulating AT2 enhanced NO production. NO inhibits NaCl absorption by: 1) activating phosphodiesterase II (PDE II), which degrades cAMP;and 2) by reducing 02'. However, the role of ATi in stimulating THAL NaCl absorption is not well understood, and whether AT2 activation inhibits transport is unknown. Elevated THAL NaCl absorption and defects in THAL NO production and signaling contribute to salt-sensitive hypertension and renal damage, but we do not know whether AT2-induced NO signaling is defective as well. We hypothesize that in animals on a normal diet the stimulatory effects ofATi activation on THAL NaCl absorption are blunted by AT2-induced NO which reduces cAMP and O2'. Defects in THAL AT2 signaling promote increases in BP, salt-sensitive hypertension and renal damage.
Aim I tests whether the levels of Ang II found in vivo in the renal outer medulla activate AT2 which blunt the stimulatory effects of ATi activation on net NaCl absorption by inhibiting trans- and paracellular transport.
Aim II tests whether AT2 activation augments NO and cGMP, and cGMP reduces NaCl absorption in part by enhancing PDE II activity which reduces cAMP.
Aim III tests whether AT2-induced NO and cGMP reduces NaCl absorption in part by diminishing ATi-stimulated O2".
Aim I V tests whether AT2-induced inhibition of THAL NaCl transport is reduced in salt-sensitive hypertension and the mechanisms involved.
These aims will be addressed using cellular and molecular biological techniques in addition to whole animal experiments. This project relates to Project I because both will study Dahl SS rats. It relates to Project II because both will study Ang II and O2". It relates to Projects III because both will study: 1) Na transport;2) Ang II;and 3) Dahl rats. Project IV will use the Administrative, Mutant Mouse, Analytical and Biostatistical Cores.

Public Health Relevance

This project is important because it addresses how Ang II regulates THAL NaCl absorption through activation of ATi and AT2 receptors. Defects in THAL NaCl absorption cause hypertension, especially salt- sensitive hypertension, and renal damage. Understanding the cellular mechanisms by which AT2 activation reduces THAL transport and how salt-sensitive hypertension changes them may lead to better treatments for this disease and for the renal damage caused by high BP.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL028982-32
Application #
8611940
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
32
Fiscal Year
2014
Total Cost
$301,777
Indirect Cost
$95,786
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
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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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