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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Henry Ford Health System
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Zenner, Zachary P; Gordish, Kevin L; Beierwaltes, William H (2018) Free radical scavenging reverses fructose-induced salt-sensitive hypertension. Integr Blood Press Control 11:1-9
Jaykumar, Ankita Bachhawat; Caceres, Paulo S; Sablaban, Ibrahim et al. (2016) Real-time monitoring of NKCC2 endocytosis by total internal reflection fluorescence (TIRF) microscopy. Am J Physiol Renal Physiol 310:F183-91
Gordish, Kevin L; Beierwaltes, William H (2016) Chronic resveratrol reverses a mild angiotensin II-induced pressor effect in a rat model. Integr Blood Press Control 9:23-31
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
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; Beierwaltes, William H (2013) The influence of extracellular and intracellular calcium on the secretion of renin. Pflugers Arch 465:59-69
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
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

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