title: Plasma and Kidney Angiotensin Peptides: Importance of the Aminopeptidase A/Angiotensin III Axis.
abstract: BACKGROUND
  The renin-angiotensin system is a complex regulatory hormonal network with a main biological peptide and therapeutic target, angiotensin (Ang) II (1-8). There are other potentially important Ang peptides that have not been well evaluated.
  
  
  METHODS
  Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for concurrent evaluation of multiple Angs downstream of Ang I (1-10) and Ang II (1-8) in kidney and plasma from wild-type (WT) mice. Angiotensin converting enzyme 2 knockout (ACE2KO) was also used as a way to examine the Angs profile in the absence of ACE2, an enzyme that cleaves both Ang I (1-10) and Ang II (1-8).
  
  
  RESULTS
  In plasma from both WT and ACE2KO, levels of Ang I (1-10), Ang III (2-8), and Ang (2-10) were the highest of all the renin-angiotensin system (RAS) peptides. The latter two peptides are products of aminopeptidase A cleavage of Ang II (1-8) and Ang I (1-10), respectively. In contrast, plasma levels of Ang II (1-8), and Ang (1-7), the product of Ang II (1-8) cleavage by ACE2, were low. In kidney from both WT and ACE2KO, Ang II (1-8) levels were high as compared to plasma levels. In the ACE2KO mice, a significant increase in either Ang II (1-8) or a decrease in Ang (1-7) was not observed in plasma or in the kidney.
  
  
  CONCLUSIONS
  RAS-focused peptidomic approach revealed major differences in Ang peptides between mouse plasma and kidney. These Ang peptide profiles show the dominance of the aminopeptidase A/Ang (2-10) and aminopeptidase A/Ang III (2-8) pathways in the metabolism of Ang I (1-10) and Ang II (1-8) over the ACE2/Ang (1-7) axis. Ang III (2-8) and other peptides formed from aminopeptidase A cleavage may be important therapeutic RAS targets.
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Wysocki
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Minghao
authors.initials: M
authors.lastname: Ye
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. d-batlle@northwestern.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Batlle
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000809:Angiotensins / Q000097:blood*; D000818:Animals; D005260:Female; D043384:Glutamyl Aminopeptidase / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D012084:Renin-Angiotensin System
chemical_list: D000809:Angiotensins; D043384:Glutamyl Aminopeptidase; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: ACE2; aminopeptidase A; angiotensin (1–7); blood pressure; hypertension.; angiotensin II; angiotensin III