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

详细信息	查看全文 | 推荐本文 |

• 作者：Brian M. Westwood ; Mark C. Chappell ; ^{mchappel@wfubmc.edu}
• 关键词：Angiotensin-(1&ndash ; 12) ; Renin ; ACE ; Neprilysin ; Ang-(1&ndash ; 7) ; Ang-(1&ndash ; 4) ; HPLC
• 刊名：Peptides
• 出版年：2012
• 期刊代码：59_01969781
• 类别：neu
• 出版时间：June, 2012
• 卷：35
• 期：2
• 页码：190-195
• 文件大小：416 K

摘要

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 ¹²⁵I-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 卤 4 and 104 卤 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 卤 9 and 310 卤 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.