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.
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.
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