The prevalence of hypertension, increases with age from 30% of U.S. adults aged 20-44 to >75% of U.S. adults above the age of 65. Less than half of elderly patients with hypertension achieve adequate blood pressure control and older hypertensive patients are significantly less likely to receive a thiazide prescription (first line anti-hypertensive) than younger patients. This suggests contemporary prescribing practices to the elderly are sub-optimal. This application will test the global hypothesis that attenuated mechanosensitive afferent renal nerve sympathoinhibitory reflexes evoke sodium chloride cotransporter-mediated renal sodium retention and age-dependent hypertension. These studies will employ our novel technique of selective afferent renal nerve ablation, a unique in-vivo surgical approach to activate the mechanosensitive afferent renal nerves, and genetic and pharmacological tools in 3, 8 and 16 month old Sprague-Dawley rats (model of normal aging) that exhibit age-dependent hypertension to provide new mechanistic insight into the pathophysiology of age- dependent hypertension. The following Specific Aims will be conducted to test this hypothesis:
Specific Aim 1 : Impairments in the renal sympathetic nerves contribute to age-dependent hypertension.
Specific Aim 2 : Attenuation of the mechanoreceptor-activated sympathoinhibitory afferent renal nerve natriuretic reno-renal reflex occurs in age-dependent hypertension.
Specific Aim 3 : Age-dependent elevations in sympathetic tone increase NCC activity, via a NE-?1-adrenoceptor-gated WNK1-OxSR1 signal transduction pathway, to evoke renal nerve-dependent sodium retention and hypertension. These hypertension focused studies are central to the mission of the NIA, which is to understand the nature of the aging processes and diseases associated with aging to extend healthy years of life. This supplement contains the new NOT-AG-20-008 Specific Aim 4: Age- dependent increases in blood pressure evoke blood brain barrier dysfunction and memory impairment in the Sprague Dawley rat model of normal aging and in the TgF344-AD rat model of Alzheimer's disease. This New Aim will address the novel hypothesis that age-dependent increases in BP evoke BBB dysfunction and cognitive impairment in the SD rat model of normal aging and in the novel rat model of Alzheimer's disease (TgF344-AD). The unique multi-disciplinary nature of our team, which combines expertise in aging, hypertension, neuroscience, will utilize novel rat models of normal aging and AD and cutting edge in vivo electrophysiology technology to comprehensively test our hypothesis. Completion of this New Aim, which will directly address weaknesses in prior research in this area, will drive a new area research in the critical area of vascular cognitive impairment and AD to support future planned R01 submissions.

Public Health Relevance

(Parent R01 A G 0 6 2 5 1 5 ) The prevalence of hypertension, which is predicted to be the leading global cause of death and disability by 2020, increases with age from 30% of U.S. adults aged 20-44 to >75% of U.S. adults above age 65, and the risk of hypertension-related mortality increases dramatically with age. This project will establish the mechanisms that operate between the sympathetic nervous system and the kidney to regulate long-term sympathetic outflow, sodium homeostasis, and blood pressure in age-dependent hypertension in a model of normal aging, the Sprague Dawley rat. Our research strategy will define an age-dependent renal sympathetic nerve mechanism through which the sympathetic nervous system regulates sodium excretion and blood pressure, and will potentially identify new therapeutic targets and approaches for the treatment of age- dependent hypertension.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Aging Systems and Geriatrics Study Section (ASG)
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Williams, John
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Boston University
Schools of Medicine
United States
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