New views, inputs, and properties: a new look at the renin-angiotensin system

Unrestricted Hypertension is called a silent killer because there are no early symptoms and it can lead to cardiovascular disease, the leading cause of morbidity worldwide. There is no cure, but several classes of medications target the renin-angiotensin system (RAS), a signaling pathway with paramount short and long-term influence over blood pressure. Renin is a hormone enzyme which controls RAS and leads to the generation of Ang II, a peptide that regulates blood pressure and electrolyte balance. RAS activity is tightly controlled to maintain homeostasis, so hypertension can be taken as a sign of RAS dysregulation due to the loss of inhibition or excessive stimulation. High sugar diets especially predispose individuals to a form of hypertension which is responsive to, or whose onset can be delayed by, RAS inhibition. Accordingly, we hypothesized that there must be a direct mechanism by which sugar metabolism causes pathological RAS activation. Since the kidney is a primary target of sugar and blood pressure disorders, the effects of both on molecular, cellular, tissue, and organ function in the kidneys were examined. We applied multi-photon fluorescence microscopy to study otherwise undetectable elements of RAS activity.; Chapter 1 characterizes an in vivo imaging based approach to evaluate renal physiological functions in healthy and hypertensive animals. Multiphoton microscopy detected perturbations in renin content and release, single nephron glomerular filtration rate, and cortical blood flow as early indicators of hypertension even before the onset of symptoms or sequelae. In Chapter 2, imaging was used to assess the hypertensive and RAS-activating capacity of a dietary sugar metabolite, uric acid. Determining the mechanism behind the uric acid-RAS interaction revealed the capability of an environmental factor to commandeer a physiological pathway to cause pathology. Chapter 3 examines prorenin, an overlooked component of RAS whose regulation has inauspicious consequences for persistent RAS activation in a setting of metabolic disequilibrium.Therefore, this study showed the direct influence of an environmental factor (diet) on physiological signaling and its potential implications for disease, prompting reconsideration of the classical understanding of RAS. The kidney is both a cause and casualty of hypertension, and a critical site for the activity and control of outside influences on blood pressure.