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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Henry Ford Health System
United States
Zip Code
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

Showing the most recent 10 out of 376 publications