The renin-angiotensin system (RAS) is a key endocrine system in the regulating blood pressure and water and sodium balance. Inappropriate expression of the RAS is thought to underlie or contribute to processes that comprise hypertension, heart failure, aging, diabetes, vascular diseases, and chronic renal injury. The RAS can be functionally partitioned into two opposing pathways - the ACE-Ang II-angiotensin type 1 receptor (AT1R) axis and the NEP/ACE2-Ang-(1-7)-MasR axis. The actions of Ang-(1- 7) ameliorate or antagonize the deleterious effects of Ang II. Ang-(1-7) lowers blood pressure, induces vasodilation via release of nitric oxide and prostaglandins, improves metabolic function, exhibits potent anti-inflammatory, anti-growth and anti-fibrotic actions, attenuates oxidative stress and improves central cardiovascular pathways such as the baroreflex. Reduced Ang-(1-7) tone may contribute to cardiovascular pathologies as much as activation of the Ang II-AT1R axis. We recently identified an Ang-(1-7) endopeptidase (A7-EP) that directly degrades Ang-(1-7) to the inactive peptide Ang-(1-4). Moreover, A7-EP did not metabolize bradykinin, neurotensin or apelin suggesting a unique specificity of the peptidase. A7-EP activity was 3-fold higher in the CSF of fetal-programmed animals (in utero glucocorticoid exposure) that exhibit higher blood pressure, reduced baroreflex function and lower Ang-(1-7) levels. These novel findings lead to the overall hypothesis that a unique A7-EP contributes to endogenous Ang-(1-7) tone through the efficient metabolism of Ang-(1-7) to Ang-(1-4) in the brain and kidney. The proposal may identify new therapeutic strategies that the block the peptidase and enhance endogenous Ang-(1-7) tone.

Public Health Relevance

Clinical Relevance: Cardiovascular disease (CVD) is leading cause of death in the US and an increasing number of infants are exposed with glucocorticoids in utero which may negatively impact their cardiovascular health in adulthood. A major target of glucocorticoids in the infant (fetal programming) is the renin-angiotensin system (RAS) and the proposed project addresses the identification and characterization of a novel enzyme that regulates key components of the RAS. Development of a specific enzyme detection assay may provide an early marker of fetal programming events in young adults, as well as selective enzyme inhibitors as a novel approach to improve cardiovascular actions.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Hypertension and Microcirculation Study Section (HM)
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Grave, Gilman D
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Wake Forest University Health Sciences
Schools of Medicine
United States
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Chappell, Mark C; Al Zayadneh, Ebaa M (2017) Angiotensin-(1-7) and the Regulation of Anti-Fibrotic Signaling Pathways. J Cell Signal 2:
South, Andrew M; Nixon, Patricia A; Chappell, Mark C et al. (2017) Antenatal corticosteroids and the renin-angiotensin-aldosterone system in adolescents born preterm. Pediatr Res 81:88-93
Brosnihan, K Bridget; Chappell, Mark C (2017) Measurement of Angiotensin Peptides: HPLC-RIA. Methods Mol Biol 1527:81-99
Sigmund, Curt D; Diz, Debra I; Chappell, Mark C (2017) No Brain Renin-Angiotensin System: Déjà vu All Over Again? Hypertension 69:1007-1010
Wilson, Bryan A; Cruz-Diaz, Nildris; Su, Yixin et al. (2017) Angiotensinogen import in isolated proximal tubules: evidence for mitochondrial trafficking and uptake. Am J Physiol Renal Physiol 312:F879-F886
Cruz-Diaz, Nildris; Wilson, Bryan A; Pirro, Nancy T et al. (2016) Identification of dipeptidyl peptidase 3 as the Angiotensin-(1-7) degrading peptidase in human HK-2 renal epithelial cells. Peptides 83:29-37
Chappell, Mark C (2016) Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute? Am J Physiol Heart Circ Physiol 310:H137-52
Wilson, Bryan A; Cruz-Diaz, Nildris; Marshall, Allyson C et al. (2015) An angiotensin-(1-7) peptidase in the kidney cortex, proximal tubules, and human HK-2 epithelial cells that is distinct from insulin-degrading enzyme. Am J Physiol Renal Physiol 308:F594-601