Renal dopamine D1 and angiotensin II AT1 receptors by regulating proximal tubular sodium transporters maintain sodium homeostasis and blood pressure. Recently we reported that exaggerated AT1 and reduced D1 receptor function in old (21-month) Fischer 344 X Brown Norway (FBN) rats were associated with increased oxidative stress and high blood pressure suggesting role of oxidative stress in this phenomenon. Our preliminary studies show that these changes are associated with increased AT1 and decreased D1 receptor mRNAs as well as higher nuclear levels of redox-sensitive transcription factors NFkB and Sp3 in proximal tubules of old rats. And, in cell culture NFkB expression plasmid increased AT1 receptor mRNA and protein while Sp3 expression plasmid decreased D1 receptor mRNA and proteins. Based upon these findings we propose to test the central hypothesis that "Activation of transcription factors NFkB and Sp3 upon oxidative stress increases AT1 receptor function (NFkB) and suppresses D1 receptor function (Sp3) thus contributing to high blood pressure in old rats. Antioxidant supplementation reduces oxidative stress, normalizes NFkB and Sp3 activity, restores AT1 and D1 receptor function, and lowers blood pressure in old rats".
Two specific aims will be undertaken to test the hypothesis.
Aim 1 will identify causative role of oxidative stress in exaggerated renal AT1 and diminished D1 receptor function contributing to high blood pressure as measured in conscious old rats.
Aim 2 will study the mechanism that NFkB and Sp3 by engaging epigenetic process activates AT1 while represses D1 receptor transcription, respectively, contributing to altered AT1 and D1 receptor function and increase in blood pressure during oxidative stress. The causative role of oxidative stress in adverse AT1 and D1 receptor function and blood pressure will be studied by reducing oxidative stress in old rats with antioxidant. The role of NFkB and Sp3 in this phenomenon will be studied by depleting these proteins with respective shRNA lentiviral particle delivery to rat kidneys and by their over-expression using respective expression vector in cell cultures. These studies should provide a better understanding of the mechanism by which oxidative stress causes hypertension which would subsequently lead to targeted therapy for hypertension.
High blood pressure is a major contributor to high morbidity and mortality in the elderly. The incidence of high blood pressure in this population group is likely to increase as the number of elderly is predicted to increase dramatically over the next few decades. Our research will identify that oxidative stress, which is a hall-mark of aging process, alters two key receptor function present in the kidney and contributes to high blood pressure in aging. The results obtained will identify future therapeutic targets as well as potential use of antioxidants to reduce blood pressure for a healthy aging process.
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