Integrated renal and neural mechanisms contributing to sodium homeostasis and blood pressure regulation
MetadataShow full item record
Hypertension affects one in two adults in the United States and contributes to more than 10% of deaths worldwide. The salt sensitivity of blood pressure, a clinical phenomenon present in one half of hypertensive patients and one quarter of normotensive individuals, predicts the development of hypertension. The prevalence of hypertension rises with age, and age-related increases in salt sensitivity and sympathetic nervous system activity, which promotes renal sodium reabsorption and plays a pathophysiological role in salt sensitivity and hypertension, have been documented. Increased mechanistic insight into the integrated renal and neural mechanisms influencing sodium homeostasis and blood pressure, particularly in aging, could yield valuable information for the phenotypically targeted treatment of hypertension. The renal nerves, comprised of the sensory afferent renal nerves (ARN) and the efferent renal sympathetic nerves, influence sodium homeostasis and blood pressure. The ARN, which include mechanosensitive and chemosensitive fibers, mediate a sympathoinhibitory reno-renal reflex that suppresses renal sympathetic nerve activity. The renal sympathetic nerves release norepinephrine, which can promote salt-sensitive hypertension in part by activating the sodium chloride cotransporter (NCC). In this thesis, Sprague Dawley rats were used as a model of normal aging to demonstrate that 1) the ARN are critical to the sympathoinhibitory and natriuretic responses to alterations in sodium homeostasis and protect against salt sensitivity of blood pressure, 2) the paraventricular nucleus of the hypothalamus may be a site of central integration of the mechanosensitive sympathoinhibitory reno-renal reflex, 3) norepinephrine promotes NCC activity through an α1-adrenoceptor-gated WNK1-OxSR1-dependent signaling pathway, driving salt-sensitive hypertension, and 4) impairments in the sympathoinhibitory reno-renal reflex may promote sympathoexcitation and NCC-mediated sodium retention, driving salt-sensitive hypertension in aging rats. Finally, data from the Genetic Epidemiology of Salt Sensitivity study were used to demonstrate that variance in the gene encoding Gαi2 proteins, which are upregulated in the paraventricular nucleus during high salt intake in salt-resistant animal models and are required for dietary sodium-evoked suppression of renal sympathetic outflow, may be a biomarker for the salt sensitivity of blood pressure in humans. Together, these findings highlight the integrated renal and neural mechanisms contributing to salt sensitivity and age-related hypertension.
RightsAttribution-NonCommercial 4.0 International