This is a revised Program Project Grant, the central theme is that """"""""endocrine, paracrine and autoerine factors produced by the epithelial, vascular smooth muscle, endothelial and interstitial cells play an important role in regulating salt and water excretion by the kidney, and thus blood pressure, by altering renal hempdynamics, changing NaCI reabsorption and mediating cross-talk between cells."""""""" The central hypothesis to be tested is that blood pressure regulation by the kidney occurs via integration of the actions of prch and anti-hypertensive agents on nephron transport, renal vascular resistance, release of renal hormones and cross-talk between epithelial and vascular cells. Defects in the integration process and/or actions of pro- and anti-hypertensive agents lead to renal dysfunction, salt retention and hypertension. This hypothesis will be tested in four projects that break new ground in our understanding of how the kidney regulates blood pressure. Project 1 will study whether increasing luminal flow in the thick ascending limb stimulates nitric oxide (NO) production by NO synthase 3, the signaling cascades involved, the effects of flow-induced NO on NaCI reabsorption, and whether a defective response to flow-stimulated NO production enhances sait retention and promotes salt-sensitive hypertension. Project 2 will test whether NO inhibits thick ascending limb NaCI reabsorption by activating cGMP-stimulated phosphodiesterase 2 (PDE2), reducing cAMP, and thus decreasing Na/K/2CI cotransport. It will also test in Dahl salt-sensitive rats whether a reduction in NOinduced inhibition of NaCI reabsorption and hypertension is caused by diminished PDE2 activity and enhanced cGMP degradation by phosphodiesterase 5. Project 3 will test whether heme oxygenases in the macula densa produce carbon monoxide (CO) and biliverdin, which act synergistically and in an autocrine manner to inhibit tubuloglomeailar feedback. It will also test whether CO acts by stimulating cGMP which inhibits Na/K/2CI cotransport, and blocks ATP release and biliverdin acts by decreasing superoxide, thereby increasing NO. Project 4 will test whether increased extracellular Ca inhibits renin release by activating Ca sensing receptors on juxtaglomerular cells which increases intracellular Ca and reduces cAMP production by inhibiting adenylyl cyclase-V and stimulating phosphodiesterase 1. These studies will be performed in vitro at the subcellular, cellular, and isolated tissue levels and in vivo using both acute and chronic models, and genetically manipulated mice. The four projects will be supported by three core units (Administrative, Molecular Biology and Analytical, and Imaging) that will facilitate the scientific effort. The Program Project Grant will provide integration of our efforts, continued collaboration and shared ideas and expertise. Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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OH, Youngsuk
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Henry Ford Health System
United States
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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
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
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 (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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