Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide component of the renin angiotensin system and the endogenous ligand for the Mas receptor. Ang-(1-7) is generated mainly via angiotensin converting enzyme 2 (ACE2)-dependent cleavage of Angiotensin (Ang) II. Studies suggest Ang-(1-7) may protect against progression of renal injury in experimental models of chronic kidney disease, although the responses may be dose dependent. The role of Ang-(1-7) in the progression of renal fibrosis in unilateral ureteral obstruction (UUO) remains unclear. We tested the hypothesis that endogenous Ang-(1-7) and low dose exogenous Ang-(1-7) would protect against renal injury in the UUO model, while high dose Ang-(1-7) would exacerbate renal injury. Male C57Bl/6 mice underwent UUO and received vehicle, the Ang-(1-7) antagonist A779, or one of three doses of Ang-(1-7) for 10 days. Treatment with A779 exacerbated renal injury as seen by increased fibronectin, transforming growth factor-β (TGF-β), and α-smooth muscle actin (α-SMA) expression, increased tubulointerstitial fibrosis scores, macrophage infiltration, apoptosis, and NADPH oxidase activity in obstructed kidneys. Paradoxically, delivery of exogenous Ang-(1-7) was associated with increased renal injury regardless of dose. Taken together, these data indicate the Mas receptor may be sensitive to concentrations of Ang-(1-7) within the obstructed kidney and that exogenous Ang-(1-7) stimulates pro-fibrotic and pro-inflammatory signalling through unclear pathways.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/23692 |
| Date | January 2013 |
| Creators | Zimmerman, Danielle |
| Contributors | Burns, Kevin, Touyz, Rhian |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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