The peptide angiotensin (1-7) [ANG (1-7)] counteracts the well-known deleterious effects of elevated angiotensin II (ANG II) levels via multiple mechanisms. As a result, there is substantial and growing interest in the use of Mas1 receptor agonists like AVE0991 and orally active formulations of ANG (1-7), [e.g. HP?CD/Ang-(1-7)] as therapeutic agents in pathological conditions characterized by high levels of angiotensin II. However, in contrast to the widely studied signal transduction mechanisms of ANG II, much less is known about the mechanisms by which Mas1 receptor agonists exert their protective effects. Of particular importance in this regard are recent findings that Mas receptor activation ameliorates oxidant stress and vascular dysfunction during conditions characterized by chronically low levels of ANG II, e.g. elevated dietary salt intake and also in the Dahl salt-sensitive (SS) rat model of human salt-sensitive hypertension. Those observations suggest that Mas receptor activation could provide a valuable therapeutic approach to treat endothelial dysfunction, oxidant stress, and renal damage in low renin salt-sensitive forms of hypertension. Our fundamental hypothesis is that Mas receptor activation will ameliorate endothelial dysfunction, vascular oxidant stress, and renal damage in male and female Dahl SS rats; and that oxidant stress, endothelial dysfunction, and renal damage will be exacerbated in male and female rats having a null mutation in the gene that codes for the Mas1 receptor, especially during exposure to high salt (HS; 4% NaCl) diet. We further hypothesize that administration of Mas receptor agonists will be ineffective in ameliorating the deleterious effects of HS diet in the Mas1R(-/-) rats and will also be ineffective in amelioriating vascular oxidant stress and endothelial dysfunction in Mas1R(-/-) rats fed low salt (LS; 0.4% NaCl) diet. The present project has two specific aims.
Specific Aim #1 is to use established techniques to provide basic vascular and renal phenotyping of a newly- developed Mas1 receptor(-/-) mutant rat in the Dahl SS genetic background during exposure to short-term and chronic HS diet.
Specific Aim #2 is to identify the impact of losing Mas receptor function on the beneficial effects of ANG (1-7) on basic vascular and renal phenotypes in male and female rats maintained on low salt and high salt diet. Development of this novel experimental model lacking Mas receptor function will provide fundamental insight into the role of the Mas receptor in maintaining vascular and renal protective mechanisms; and will also provide an extremely valuable resource to evaluate the potential efficacy of Mas receptor agonists in ameliorating vascular dysfunction, oxidant stress, and renal damage in low renin salt sensitive forms of hypertension. When completed, this project will provide a unique and valuable experimental resource, specifically an experimental animal model that is uniquely suited to obtain fundamental knowledge regarding the role of the Mas receptor in mediating its protective effects in the cardiovascular system, the kidney, and other cell and organ systems of interest to multiple NIH institutes.
Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers have long been used to combat vascular oxidant stress, prevent kidney damage, and lower blood pressure in hypertension arising from abnormally high levels of angiotensin II in the blood. In recent years, there has been growing interest in the use of agents that activate the Mas1 receptor for angiotensin (1-7), a peptide component of the renin-angiotensin system that directly opposes the effects of elevated levels of angiotensin II. This project will use genetic techniques to eliminate Mas1 Receptor function in salt-sensitive rats, in order to understand the role of this receptor in maintaining normal function of the blood vessels and kidneys; and to gain an increased understanding of the effects of Mas1 receptor agonists as potential therapeutic agents in human cardiovascular diseases.
| Bukowy, John D; Dayton, Alex; Cloutier, Dustin et al. (2018) Region-Based Convolutional Neural Nets for Localization of Glomeruli in Trichrome-Stained Whole Kidney Sections. J Am Soc Nephrol 29:2081-2088 |
| Allen, Linda A; Schmidt, James R; Thompson, Christopher T et al. (2018) High salt diet impairs cerebral blood flow regulation via salt-induced angiotensin ii suppression. Microcirculation :e12518 |
