Project 1 examines the role of nitric oxide (NO) in the regulation of blood flow to the renal medulla. Although the medulla receives only about 5-10% of total renal blood flow, we have shown that perfusion of this region plays an important role in the regulation of sodium excretion and in the long-term control of arterial pressure. The mechanisms which regulate medullary blood flow remain poorly understood, but NO appears to be importantly involved. We have shown that nitric oxide synthase (NOS) activity is substantially greater in the medulla than in the cortex. Furthermore, chronic inhibition of medullary NOS activity greatly reduces medullary blood flow and results in sodium retention and hypertension. The goal of this project is to determine in medullary [NO] plays an important role in the normal homeostatic regulation of medullary flow by moderating the effects of vasoconstrictor hormones. such as angiotensin II (ANGII) and norepinephrine (NE), which may be trapped and concentrated by the counter-current vasa recta circulation. We hypothesize that these compounds stimulate the release of NO which in turn buffers reductions of medullary flow, tissue P0/2, and prevents hypertension. The application of techniques ranging from the molecular to the whole animal will enable examination of this hypothesis. We have developed a method for the direct tissue measurement of NO concentrations within the renal medulla in both anesthetized and conscious instrumented rats (microdialysis oxyHb-NO trapping). Implanted optical fibers and laser-Doppler flowmetry will also be used to measure regional blood flow changes in the renal medulla and cortex in unanesthetized rats. Techniques have also been developed to quantify regional changes of NOS gene expression, protein expression, enzyme activity and L-arginine concentrations in whole tissue and in isolated medullary microvessels and tubules of the renal medulla. Studies will determine if circulating angiotensin II (ANGII) and norepinephrine (NE) stimulate medullary NO production which buffers against acute reductions of regional blood flow. We will determine whether medullary NO serves to protect flow to the renal medulla and prevention hypertension in the face of chronic elevations of ANGII or NE. Towards this end, we will compare the influence of ANGII and NE on medullary blood flow in rats in which medullary NOS production is blunted pharmacologically with L-NAME and in the Dahl S rat, a non-pharmacological model which we find has a reduced capacity to release NO. Localization and quantification of acute and chronic effects of ANGII and NE on medullary microvascular and tubular NOS mRNA (nNOS, iNOS, eNOS), NOS enzyme activity and protein expression will be determined in Sprague Dawley rats. The proposed project builds upon the unique interdisciplinary and collaborative strengths of this PPG and will provide important new insights regarding the role of NO in the regulation of renal medullary blood flow and the long-term control to arterial pressure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Medical College of Wisconsin
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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
Mladinov, Domagoj; Liu, Yong; Mattson, David L et al. (2013) MicroRNAs contribute to the maintenance of cell-type-specific physiological characteristics: miR-192 targets Na+/K+-ATPase ?1. Nucleic Acids Res 41:1273-83

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