In hypertension, high glomerular capillary pressure (PGC) leads to glomerulosclerosis. In African-Americans with salt-sensitive (SS) hypertension, high salt intake causes an increase in estimated PQC, which could explain their high rate of hypertensive renal disease. Dahl SS rats on high salt intake have hypertension, high PGC and significant glomerular injury compared to SHR with similar blood pressure. Connecting tubule glomerular feedback (CTGF) is a cross-talk that dilates the afferent arteriole (Af-Art) when Na is increased in the connecting tubule (CNT). General hypothesis: In SS hypertension, during high salt intake there is an imbalance between factors that cause Af-Art constriction (myogenic response and TGF) versus dilatation (CTGF) in favor of the latter, leading to an increase in PGC snd glomerular damage.
Aim I, Hypothesis, In normotensive animals, chronic high salt intake causes TGF resetting due to heightened CTGF via increased release of EETs and PGE2 by the CNT. Mice with a gain-of-function mutation of ENaC have increased CTGF and reduced TGF, while mice with deletion of ENaC in the CNT have decreased or no CTGF and enhanced TGF.
Aim II, hypothesis: In hypertensive Dahl SS rats CTGF is increased, causing TGF resetting leading to increases in PGC and glomerular damage. Conversely, in SHR CTGF is decreased, causing an enhancement of myogenic response and TGF which in turn decreases PGC and protects the glomerulus from damage. In SHR, high salt will increase CTGF, causing attenuation ofthe myogenic response, TGF resetting, increased PGC, and glomerular damage. In Ang ll-induced hypertension in mice with increased ENaC activity, glomerular damage will be greater due to an increase in CTGF, while in mice with selectively decreased ENaC in the CNT glomerular damage will be lower, due to a decrease in CTGF.
Aim III, hypothesis: In hypertensive Dahl SS rats, CTGF is augmented due to increases in ENaC, COX-2 and PGE2. In contrast, in SHR CTGF is attenuated due to increased soluble epoxide hydrolase and decreased EET release. Project III is closely related to: 1) I and IV which also study Dahl SS;2) I and II which also study the pathogenesis of EOD;and II which also studies arachidonic acid metabolites. Project III will use all 4 Cores.

Public Health Relevance

In the United States, over one-fourth of adults diagnosed with hypertension have moderate to severe chronic kidney disease. Hypertension is the second leading cause of end-stage renal disease (ESRD). Thus understanding how salt-sensitive hypertension, via changes in renal microcirculation, leads to glomerular damage has great scientific and medical relevance.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL028982-31A1
Application #
8460617
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-02-15
Budget End
2014-01-31
Support Year
31
Fiscal Year
2013
Total Cost
$369,335
Indirect Cost
$117,229
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

Showing the most recent 10 out of 352 publications