Since the inception of this PPG in 1982, the overall goal of this program has been to achieve an understanding of the long-term regulation of arterial pressure and the consequences of high blood pressure. The unifying hypothesis of the present grant centers on the concept that the kidney controls the long-term level of arterial pressure and when genetically predisposed salt intake can importantly influence kidney function and the structure and function of the systemic vasculature. Project 1 will utilize Dahl salt-sensitive rats (SS) to study how a high salt diet may stimulate excess production of reactive oxygen species (ROS) in the renal medullary thick ascending limb (mTAL) leading to reduction of blood flow to the renal medulla, reduction in sodium excretion and hypertension. Project 2 hypothesizes that during the early phase of saltinduced hypertension an inflammatory process is initiated by infiltrating macrophages that produces angiotensin II (ANGII) that stimulates the production of ROS thereby increasing the severity of hypertension and renal injury. Project 3 will search for a mutation in one of the cytochrome P4504A genes (CYP4A) that is the underlying genetic defect in the SS rat that plays an important causal role in the impaired pressurenatriuresis and the development of hypertension. Project 4 examines the permissive role that ANGII plays in maintaining normal vascular reactivity and how defects in the SS renin allele lead to increased oxidative stress and impaired vascular relaxation. Project 5 focuses on the microcirculation and the mechanisms that control and alter organ and tissue perfusion in hypertension and the impact that reductions in ANGllstimulated O2 inhibit the VEGF signaling pathway leading to microvessel rarefaction and inhibition of angiogenesis that is found in the SS rat. Each of these projects utilize unique genetic rat strains (consomic, congenic, and transgenic) that provide the trait of interest and a genetically defined control strain. Hypertension affects more than 50 million Americans and remains largely uncontrolled in 75% of patients in North America leading to an increased incidence of stroke, heart, and renal disease, that contribute to escalating health care costs. The program reflects a long-standing experience of shared ideas in a synergistic environment aimed toward advancing our understanding of hypertension and the identification of novel targets for drug design that may better control this disease.

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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Medical College of Wisconsin
Schools of Medicine
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He, Xiaofeng; Liu, Yong; Usa, Kristie et al. (2014) Ultrastructure of mitochondria and the endoplasmic reticulum in renal tubules of Dahl salt-sensitive rats. Am J Physiol Renal Physiol 306:F1190-7
Liu, Yong; Liu, Pengyuan; Yang, Chun et al. (2014) Base-resolution maps of 5-methylcytosine and 5-hydroxymethylcytosine in Dahl S rats: effect of salt and genomic sequence. Hypertension 63:827-38
Rudemiller, Nathan; Lund, Hayley; Jacob, Howard J et al. (2014) CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. Hypertension 63:559-64
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Rajapakse, Niwanthi W; Mattson, David L (2013) Role of cellular L-arginine uptake and nitric oxide production on renal blood flow and arterial pressure regulation. Curr Opin Nephrol Hypertens 22:45-50
Orozco, Ludwig D; Liu, Huiling; Perkins, Eddie et al. (2013) 20-Hydroxyeicosatetraenoic acid inhibition attenuates balloon injury-induced neointima formation and vascular remodeling in rat carotid arteries. J Pharmacol Exp Ther 346:67-74
Mattson, David L; Lund, Hayley; Guo, Chuanling et al. (2013) Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage. Am J Physiol Regul Integr Comp Physiol 304:R407-14
Liang, Mingyu; Cowley Jr, Allen W; Mattson, David L et al. (2013) Epigenomics of hypertension. Semin Nephrol 33:392-9
Pavlov, Tengis S; Levchenko, Vladislav; O'Connor, Paul M et al. (2013) Deficiency of renal cortical EGF increases ENaC activity and contributes to salt-sensitive hypertension. J Am Soc Nephrol 24:1053-62
Jia, Ping; Teng, Jie; Zou, Jianzhou et al. (2013) Intermittent exposure to xenon protects against gentamicin-induced nephrotoxicity. PLoS One 8:e64329

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