Hypertension affects 1 in 3 adults and is the single greatest risk factor for premature death. Salt-sensitive hypertension occurs in approximately 50% of hypertensive patients and results in a 3-fold increase in the risk of adverse cardiovascular events. However, the pathophysiology of salt-sensitive hypertension remains to be fully elucidated. There has been increased interest in the interaction between the sympathetic nervous system and the kidney and how that interaction mediates sodium excretion to drive the development of salt-sensitivity. Previous studies show that sympathetic over-activity increases expression of the sodium chloride cotransporter (NCC) resulting in increased NCC-mediated sodium reabsorption, and the development of salt-sensitive hypertension. In this thesis, I show the effect of increased norepinephrine (NE) and high salt intake in salt-resistant vs. salt-sensitive rat phenotypes on blood pressure regulation, NCC activity, and the adrenoreceptor-mediated regulatory kinase network signal transduction pathway. A high salt diet 1) exacerbates NE-induced hypertension in salt-resistant Sprague-Dawley (SD) rats and 2) results in hypertension in Dahl salt-sensitive (DSS) rats. In contrast to salt-resistant phenotypes (SD & Dahl salt-resistant), dietary sodium-evoked suppression of NCC expression and activity is prevented in salt-sensitive rats (SD-NE infusion & DSS) - I show that this occurs through a failure of a high salt intake to suppress renal OxSR1, SPAK, and WNK1 (NCC regulatory proteins). I demonstrate that α1-adrenoreceptors are responsible for mediating the salt-sensitive component of hypertension and restore dietary sodium-evoked suppression of the NCC via a predominant OxSR1 pathway. Chronic β-adrenoreceptor antagonism significantly reduces blood pressure in NE-mediated hypertension. How the body senses salt remains unknown, but my data show that selective removal of the afferent renal nerves prevents dietary sodium-evoked suppression of NCC expression and activity resulting in salt-sensitive hypertension, suggesting that the afferent renal nerves play an important role as a sodium-sensing mechanism. Overall, these data demonstrate that attenuated afferent renal nerve feedback drives renal efferent nerve release of NE to prevent the downregulation of the NCC via an α1-adrenergic receptor-gated WNK1-OxSR1 signal transduction pathway to evoke the development of salt-sensitive hypertension.

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.