title: Divergent pathways for the angiotensin-(1-12) metabolism in the rat circulation and kidney.
abstract: Evidence of endogenous angiotensin-(1-12) [Ang-(1-12)] may necessitate revision of the accepted view that Ang I is the immediate peptide product derived from the precursor protein angiotensinogen. As the processing of this peptide has not been fully elucidated, we characterized Ang-(1-12) metabolism in the serum and kidney of the mRen2.Lewis rat, a model of high circulating renin and ACE expression. A sensitive HPLC-based method to detect the metabolism ex vivo of low concentrations of (125)I-labeled Ang-(1-12) was utilized. Ang-(1-12) processing to serum did not reveal the participation of renin; however, serum ACE readily converted Ang-(1-12) to Ang I with subsequent metabolism to Ang II. Ang I and Ang II forming activities for serum ACE were 102±4 and 104±3 fmol/ml/min serum (n=3), respectively, and both products were abolished by the potent ACE inhibitor lisinopril. The metabolism of Ang-(1-12) in renal cortical membranes also revealed the formation of Ang I; however, the main products were Ang-(1-7) and Ang-(1-4) at 129±9 and 310±12 fmol/mg/min protein (n=4), respectively. Neprilysin inhibition abolished these products and substantially reduced the overall metabolism of Ang-(1-12). Incubation of Ang-(1-12) with either human or mouse neprilysin revealed identical products. We conclude that endogenous Ang-(1-12) may contribute to the expression of biologically active angiotensins through a renin-independent pathway. The preferred route for Ang-(1-12) metabolism likely reflects the relative tissue content of ACE and neprilysin.
authors.affiliation: The Hypertension & Vascular Research Center, Wake Forest University Health Science Center, Winston-Salem, NC 27157, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Westwood
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
mesh_terms: D000803:Angiotensin I / Q000097:blood / Q000378:metabolism*; D000804:Angiotensin II / Q000097:blood / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000378:metabolism; D000809:Angiotensins / Q000097:blood / Q000378:metabolism*; D000818:Animals; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism*; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D015260:Neprilysin / Q000494:pharmacology; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D012083:Renin / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D010446:Peptide Fragments; C515557:proangiotensin-12, rat; D000808:Angiotensinogen; D000804:Angiotensin II; D000803:Angiotensin I; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D015260:Neprilysin