The overall goal of this project is to achieve an understanding of the relationship between nitric oxide (NO) release from endothelial NO synthase (eNOS), the circulating levels of angiotensin II (Angll), and the regulation of arterial blood pressure. This goal will be addressed by combining newly developed methodology to measure fluid and electrolyte homeostasis and blood pressure in conscious mice with a variety of unique cellular, molecular, and physiological techniques. We will test the hypothesis that NO produced from eNOS in endothelial cells is the primary buffering mechanism against the prohypertensive actions of Angll. As a corollary to this primary hypothesis, we further theorize that selective inhibition, or elimination, of NO production in endothelial cells will lead to hypertension that is independent of NaCI intake while inhibition of NOS in renal tubular structures will lead to sodium-sensitive hypertension.
Aim 1 will utilize unique cellular and molecular techniques to characterize the distribution of NOS isoforms and NOS enzymatic activity in microdissected renal tubular and vascular segments of wild-type (WT) and eNOS null mutant (-/-) mice and to determine the changes in NOS expression in these segments during alterations in circulating Angll and/or sodium chloride intake.
Aim 2 will employ novel techniques to perform in vivo microdialysis in anesthetized mice and sample arterial blood from conscious mice to characterize the interaction between circulating Angll, dietary sodium intake, and renal NO production in WT and eNOS(-/-)mice.
Aim 3 will determine the functional effects of changes in circulating Angll and/or dietary sodium intake in WT and eNOS(-/-) mice using methodology which permits long-term monitoring of cardiovascular/renal variables in conscious mice. Together, this novel combination of experimental methods will be used to determine the important role of NO derived from eNOS in the modulation of the vasoconstrictor and prohypertensive effects of Angll in the conscious mouse. Results of these studies in conscious mice should provide new understanding of the role of eNOS-derived NO in the control of renal function and arterial blood pressure. Moreover, the results of these studies may also provide important insight into the causes of hypertension and hypertension-related complications that are a leading cause of death and morbidity in the US.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062803-03
Application #
6888979
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Ketchum, Christian J
Project Start
2003-07-01
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$206,391
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
Abais-Battad, Justine M; Lund, Hayley; Fehrenbach, Daniel J et al. (2018) Parental Dietary Protein Source and the Role of CMKLR1 in Determining the Severity of Dahl Salt-Sensitive Hypertension. Hypertension :HYPERTENSIONAHA11811994
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
Das, Satarupa; Mattson, David L (2014) Exogenous L-arginine attenuates the effects of angiotensin II on renal hemodynamics and the pressure natriuresis-diuresis relationship. Clin Exp Pharmacol Physiol 41:270-8
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
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
Stelloh, Cary; Allen, Kenneth P; Mattson, David L et al. (2012) Prematurity in mice leads to reduction in nephron number, hypertension, and proteinuria. Transl Res 159:80-9
De Miguel, Carmen; Guo, Chuanling; Lund, Hayley et al. (2011) Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of hypertension and renal disease. Am J Physiol Renal Physiol 300:F734-42
De Miguel, Carmen; Lund, Hayley; Mattson, David L (2011) High dietary protein exacerbates hypertension and renal damage in Dahl SS rats by increasing infiltrating immune cells in the kidney. Hypertension 57:269-74
Rajapakse, N W; Mattson, D L (2011) Role of L-arginine uptake mechanisms in renal blood flow responses to angiotensin II in rats. Acta Physiol (Oxf) 203:391-400
De Miguel, Carmen; Das, Satarupa; Lund, Hayley et al. (2010) T lymphocytes mediate hypertension and kidney damage in Dahl salt-sensitive rats. Am J Physiol Regul Integr Comp Physiol 298:R1136-42

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