Divergent pathways for the angiotensin-(1-12) metabolism in the rat circulation and kidney

作者：Westwood Brian M; Chappell Mark C^*

来源：Peptides, 2012, 35(2): 190-195.

DOI：10.1016/j.peptides.2012.03.025

• Angiotensin-(1-12)
• Renin
• ACE
• Neprilysin
• Ang-(1-7)
• Ang-(1-4)
• HPLC

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 I-125-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.

• 出版日期2012-6