In 20% of the population, high consumption of salt leads to the development of hypertension. This is due to inability of the kidney to excrete excess salt. Animal models of salt-sensitive hypertension exhibit abnormally enhanced NaCI absorption in the loop of Henle, including the thick ascending limb (THAI). NaCI absorption by the THAI is mediated primarily by the Na/K/2CI cotransporter, NKCC2. cAMP enhances NaCI absorption by stimulating NKCC2, whereas the natriuretic factor NO decreases NaCI absorption by inhibiting NKCC2. In the Dahl salt-sensitive (SS)rat,the inhibitory effect of NO on NaCI reabsorption by the THAI is diminished. In normal animals, the cGMP-stimulated phosphodiesterase 2 (PDE2) mediates the inhibitory effect of NO on THAL NaCI reabsorption by decreasing cAMP. Phosphodiesterase 5 (PDE 5) may oppose the effect of NO by degrading cGMP. It is not clear why the inhibitory effect of NO on NaCI reabsorption by the THAL is decreased in Dahl SS rats. We hypothesize that NO inhibits thick ascending limb NaCI reabsorption by activating PDE 2 which reduces cAMP. In SS rats, NO-induced inhibition of NaCI reabsorption is decreased due to diminished PDE 2 activity. In addition, in SS rats enhanced PDE 5 degrades cGMP, further blunting PDE 2 activation by NO. Reduced action of NO during a high-salt diet contributes to salt-sensitive hypertension. This hypothesis will be tested in 4 aims.
Aim I. Hypothesis: In SS rats, the inhibitory effect of NO on NaCI reabsorption and luminal membrane NKCC2 in the THAL is decreased due to impaired cAMP degradation.
Aim II. Hypothesis: In SS rats, diminished PDE 2 activity decreases the effect of NO on NaCI reabsorption.
Aim III. Hypothesis: In SS rats, enhanced PDE 5 activity lowers cGMP and reduces PDE 2 activation by NO, further decreasing the inhibitory effect of NO on NaCI reabsorption.
Aim I V. Hypothesis: In SS rats fed a high-salt diet, diminished PDE 2 and enhanced PDE 5 activity decrease the inhibitory effect of NO on NaCI reabsorption, contributing to the hypertension in this strain. This project relates to the central theme because it studies how a defect in an autocrine anti-hypertensive mechanism enhances renal salt reabsorption and contributes to hypertension. The information from this project will be integrated with that from all other projects. It will use all of the cores. Our findings will focus the search for the genes involved in salt-sensitive hypertension and may lead to new therapies for the treatment of high blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL090550-05
Application #
8448086
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$296,215
Indirect Cost
$94,021
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Gordish, Kevin L; Beierwaltes, William H (2014) Resveratrol induces acute endothelium-dependent renal vasodilation mediated through nitric oxide and reactive oxygen species scavenging. Am J Physiol Renal Physiol 306:F542-50
Ortiz-Capisano, M Cecilia; Reddy, Mahendranath; Mendez, Mariela et al. (2013) Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP(3) pathway and the ryanodine receptor. Am J Physiol Renal Physiol 304:F248-56
Atchison, Douglas K; Beierwaltes, William H (2013) The influence of extracellular and intracellular calcium on the secretion of renin. Pflugers Arch 465:59-69
Ortiz-Capisano, M Cecilia; Atchison, Douglas K; Harding, Pamela et al. (2013) Adenosine inhibits renin release from juxtaglomerular cells via an A1 receptor-TRPC-mediated pathway. Am J Physiol Renal Physiol 305:F1209-19
Ramseyer, Vanesa D; Garvin, Jeffrey L (2013) Tumor necrosis factor-ýý: regulation of renal function and blood pressure. Am J Physiol Renal Physiol 304:F1231-42
Beierwaltes, William H (2013) Endothelial dysfunction in the outer medullary vasa recta as a key to contrast media-induced nephropathy. Am J Physiol Renal Physiol 304:F31-2
Atchison, Douglas K; Harding, Pamela; Beierwaltes, William H (2013) Vitamin D increases plasma renin activity independently of plasma Ca2+ via hypovolemia and *-adrenergic activity. Am J Physiol Renal Physiol 305:F1109-17
Cabral, Pablo D; Garvin, Jeffrey L (2013) Less potassium coming out, less sodium going in: phenotyping ROMK knockout rats. Hypertension 62:240-1
Ren, Yilin; D'Ambrosio, Martin A; Wang, Hong et al. (2012) Mechanisms of carbon monoxide attenuation of tubuloglomerular feedback. Hypertension 59:1139-44
Beierwaltes, William H (2012) Are microRNAs the key to transforming renin progenitor cells in the afferent renal circulation? Am J Physiol Renal Physiol 302:F27-8

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