In this proposed study, we aim to examine the hypothesis that 'Salt-sensitive hypertension develops due to enhanced oxidative stress resulting from an imbalance between intrarenal nitric oxide (NO) and superoxide (O2-) which are regulated reciprocally in the kidney.'The proposed experiments will examine the role of O2- and NO interaction in the patho-physiology of salt-sensitive hypertension and are focused on to characterize and delineate these interactions both at oxidative and antioxidative enzymes levels as well as on assessment of functional consequences to altered enzyme activities in the kidney. Using an integrated approach involving acute and chronic experiments in rats and knockout mice lacking genes for NO synthase NADPH oxidase, Superoxide dismutase and TNF-a, we plan to evaluate renal and systemic responses to various agents (Angiotensin II, peroxynitrite, inhibitors of O2- and NO production) that will critically delineate the role of these endogenous factors in salt-sensitivity. Acute renal studies includes assessment of clearance and hemodynamic techniques that will be enhanced by applications of needle laser- Doppler flowmetry to measure regional blood flow, NO electrode to determine tissue NO activity, microdialysis probe to assess interstitial fluid concentrations of O2- and NO metabolites. In chronic experiments in mice and rats, systemic blood pressure will be monitored by the implanted radiotelemetry and daily urine output will be determined using metabolic cages. Animals will be maintained at diets of varying salt content to delineate the relationship between salt intake, oxidative stress and the mechanism of hypertension. Protein expressions and mRNA levels of the oxidative and nitrosative enzymes in renal tissues will be determined by Western blot and RT-PCR analyses. With these approaches, we hope to obtain an improved understanding of how O2- and NO interact to produce a coordinated regulation of kidney function, imbalance of which may be involved in the patho-physiology of salt-sensitivity and hypertension. Public health research relevance: Hypertension is a leading cause of death, disability and renal failure affecting one-fifth population in US. Salt-sensitivity is critically linked to the development of hypertension. This proposed research will examine the mechanism of salt-sensitivity and the results may help to develop effective therapy for hypertension.
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