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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL029587-28
Application #
7797590
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Thrasher, Terry N
Project Start
1993-05-31
Project End
2013-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
28
Fiscal Year
2010
Total Cost
$1,596,932
Indirect Cost
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Fan, Fan; Roman, Richard J (2017) Effect of Cytochrome P450 Metabolites of Arachidonic Acid in Nephrology. J Am Soc Nephrol 28:2845-2855
Fan, Fan; Pabbidi, Mallikarjuna R; Ge, Ying et al. (2017) Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries. Am J Physiol Renal Physiol 312:F971-F981
Rudemiller, Nathan P; Mattson, David L (2015) Candidate genes for hypertension: insights from the Dahl S rat. Am J Physiol Renal Physiol 309:F993-5
Cowley Jr, Allen W; Abe, Michiaki; Mori, Takefumi et al. (2015) Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension. Am J Physiol Renal Physiol 308:F179-97
Neuner, Sarah M; Wilmott, Lynda A; Hope, Kevin A et al. (2015) TRPC3 channels critically regulate hippocampal excitability and contextual fear memory. Behav Brain Res 281:69-77
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
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
Lakshmikanthan, Sribalaji; Zieba, Bartosz J; Ge, Zhi-Dong et al. (2014) Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure. Arterioscler Thromb Vasc Biol 34:1486-94
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
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

Showing the most recent 10 out of 455 publications