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STUDIES ON ANGIOTENSIN-(1-7) AND MITOCHONDRIA: THE ROLE OF AN INTRACELLULAR RENIN-ANGIOTENSIN SYSTEM WITHIN THE KIDNEY

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abstract
Several therapies we have available to treat high blood pressure and the resulting kidney failure target a classic circulating hormonal system - the renin-angiotensin System (RAS), and specifically, the ACE-Ang II-AT1 receptor axis. We have focused strategically on investigating novel intracellular pathways by which Ang-(1-7) is generated and degraded since this alternative pathway within the kidney and other tissues may antagonize the Ang II-AT1 receptor mediated actions. We recently identified the presence of a novel enzyme activity in the brain that degrades Ang-(1-7) and is negatively correlated with central Ang-(1-7) levels and blood pressure. Moreover, seminal studies as a part of my graduate work identified this enzyme activity in the kidney, specifically in the proximal tubules and in a human proximal tubule cell line. Utilizing the human tubule cells, we purified and identified the Ang-(1-7) degrading activity as Dipeptidyl-Peptidase 3 (DPP 3). Given the bioactive role of Ang-(1-7) counteracting the deleterious effects of Ang II, we further established that the beneficial intracellular actions of Ang-(1-7) may reflect the mitochondria. Thus, we demonstrated that mitochondria isolated from sheep renal cortex expressed RAS components and contained the molecular machinery to produce Ang-(1-7) intracellularly within the kidney that include the endopeptidases neprilysin (NEP) and thimet oligopeptidase (TOP) that process Ang I directly to Ang-(1-7).
subject
angiotensin-(1-7)
intracellular
kidney
mitochondria
proximal tubules
renin-angiotensin system
contributor
Wilson, Bryan Anthony (author)
Chappell, Mark C (committee chair)
Rose, James C (committee member)
Taylor, Robert N (committee member)
Brosnihan, K Bridget (committee member)
date
2016-05-21T08:35:34Z (accessioned)
2016-05-21T08:35:34Z (available)
2016 (issued)
degree
Molecular Medicine and Translational Science (discipline)
identifier
http://hdl.handle.net/10339/59269 (uri)
language
en (iso)
publisher
Wake Forest University
title
STUDIES ON ANGIOTENSIN-(1-7) AND MITOCHONDRIA: THE ROLE OF AN INTRACELLULAR RENIN-ANGIOTENSIN SYSTEM WITHIN THE KIDNEY
type
Dissertation

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