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1 Winston-Salem, North Carolina, United States; Hypertension & Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
2 Hypertension & Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
3 Hypertension & Vascular Discease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
4 Depts. of Obstetrics/Gynecology and Physiology/Pharmacology, Wake Forest University School of Medicine, Winston-Salem,, North Carolina, United States
5 Hyperension & Vascular Disease Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States
* To whom correspondence should be addressed. E-mail: mchappel{at}wfubmc.edu.
Despite the evidence that ACE2 is a component of the renin-angiotensin system (RAS), the influence of ACE2 on angiotensin metabolism within the kidney is not well known, particularly in experimental models other than rats or mice. Therefore, we investigated the metabolism of the angiotensins in isolated proximal tubules, urine and serum from sheep. Radiolabeled 125I-Ang I was hydrolyzed primarily to Ang II and Ang-(1-7) by ACE and neprilysin, respectively in sheep proximal tubules. The ACE2 product Ang-(1-9) from Ang I was not detected in the absence or presence of ACE and neprilysin inhibition. In contrast, the proximal tubules contained robust ACE2 activity that converted Ang II to Ang-(1-7). Immunoblots utilizing an N-terminal directed ACE2 antibody revealed a single 120 kilodalton band in proximal tubule membranes. Ang-(1-7) was not a stable product in the tubule preparation and was rapidly hydrolyzed to Ang-(1-5) and Ang-(1-4) by ACE and neprilysin, respectively. Comparison of activities in the proximal tubules with a non-saturating concentrations of substrate revealed equivalent activities for ACE [Ang I to Ang II: 248± 17 fmol/mg/min] and ACE2 [Ang II to Ang-(1-7): 253 ± 11 fmol/mg/min], but lower neprilysin activity [Ang II to Ang-(1-4): 119 ± 24 fmol/mg/min; p<0.05 versus ACE or ACE2]. Urinary metabolism of Ang I and Ang II was similar to the proximal tubules; soluble ACE2 activity was also detectable in sheep serum. In conclusion, sheep tissues contain abundant ACE2 activity that converts Ang II to Ang-(1-7), but does not participate in the processing of Ang I into Ang-(1-9).
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