We previously reported that sodium excretion is significantly correlated to the excretion of nitrate/nitrite (metabolites of nitric oxide) in normotensive young adults. This association of the nitric oxide pathway with sodium excretion in humans led us to probe the mechanisms of how this mediator acts in the physiological response to changes in sodium intake in animal models. It was previously shown that the inner medullary collecting duct has the highest nitric oxide synthase (NOS) activity in the rat kidney. All three NOS isoforms are expressed in the collecting duct. Loss of functional NOS1 through pharmacological inhibition in rats delays the excretion of sodium and blunts nitrite/nitrate excretion following an acute salt challenge. Since the final control of sodium excretion occurs in the collecting duct, we have recently created collecting duct specific NOS1 knockout (CD NOS1 KO) mice. These mice were generated by the cre-lox technology in which the floxed exon 6 NOS1 mouse was mated with the aquaporin 2-cre mouse resulting in a selective knockout of NOS1 in the renal collecting duct tubules. Our preliminary data indicates that the CD NOS1 KO mice are hypertensive when compared to the control mice.
The first aim of this 2 year proposal is to test the hypothesis that the CD NOS1 KO mice will exhibit a salt-sensitive hypertensive phenotype. We also predict that the pressure-dependent natriuresis and diuresis is dysfunctional in the CD NOS1 KO mice when compared to the control mice. Several NOS1 splice variants are known to be expressed in the kidney. Our preliminary data demonstrates that NOS1b is the predominant splice variant expressed in the mouse medulla. Commercially available NOS1a knockout mice do not have any blood pressure anomaly, yet the CD NOS1 KO mice display a hypertensive phenotype and do not express any NOS1 variants. Thus, the second aim of this 2 year proposal is to test the hypothesis that the NOS1b splice variant contributes to the control of sodium reabsorption in the collecting duct.

Public Health Relevance

Salt-sensitive hypertension afflicts a majority of our population and is not readily controlled by the current therapies. Our proposed work will delineate a novel molecular pathway that controls sodium excretion and blood pressure. These studies may ultimately lead to new approaches for treating salt-sensitive hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060653-10
Application #
7851385
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
1998-07-01
Project End
2011-09-30
Budget Start
2010-07-01
Budget End
2011-09-30
Support Year
10
Fiscal Year
2010
Total Cost
$367,500
Indirect Cost
Name
Georgia Regents University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Spradley, Frank T; Ho, Dao H; Pollock, Jennifer S (2016) Dahl SS rats demonstrate enhanced aortic perivascular adipose tissue-mediated buffering of vasoconstriction through activation of NOS in the endothelium. Am J Physiol Regul Integr Comp Physiol 310:R286-96
Hyndman, Kelly A; Xue, Jing; MacDonell, Alexander et al. (2013) Distinct regulation of inner medullary collecting duct nitric oxide production from mice and rats. Clin Exp Pharmacol Physiol 40:233-9
Hyndman, Kelly A; Pollock, Jennifer S (2013) Nitric oxide and the A and B of endothelin of sodium homeostasis. Curr Opin Nephrol Hypertens 22:26-31
Spradley, F T; Kang, K-T; Pollock, J S (2013) Short-term hypercaloric diet induces blunted aortic vasoconstriction and enhanced vasorelaxation via increased nitric oxide synthase 3 activity and expression in Dahl salt-sensitive rats. Acta Physiol (Oxf) 207:358-68
De Miguel, C; Foster, J M; Carmines, P K et al. (2013) Interaction between NO synthase and NADPH oxidase in control of sodium transport by the renal thick ascending limb during diabetes. Acta Physiol (Oxf) 209:148-55
Spradley, Frank T; De Miguel, Carmen; Hobbs, Janet et al. (2013) Mycophenolate mofetil prevents high-fat diet-induced hypertension and renal glomerular injury in Dahl SS rats. Physiol Rep 1:e00137
Spradley, Frank T; White, John J; Paulson, William D et al. (2013) Differential regulation of nitric oxide synthase function in aorta and tail artery from 5/6 nephrectomized rats. Physiol Rep 1:e00145
Hyndman, Kelly A; Boesen, Erika I; Elmarakby, Ahmed A et al. (2013) Renal collecting duct NOS1 maintains fluid-electrolyte homeostasis and blood pressure. Hypertension 62:91-8
Hyndman, Kelly A; MacDonell, Alexander H; Pollock, Jennifer S (2012) Extracellular signal-regulated kinases 1/2 signaling pathways are not involved in endothelin regulation of mouse inner medullary collecting duct nitric oxide production. Life Sci 91:578-82
Kittikulsuth, Wararat; Pollock, Jennifer S; Pollock, David M (2012) Loss of renal medullary endothelin B receptor function during salt deprivation is regulated by angiotensin II. Am J Physiol Renal Physiol 303:F659-66

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