Pathways for angiotensin-(1-7) metabolism in pulmonary and renal tissues
Pathways for angiotensin-(1-7) metabolism in pulmonary and renal tissues
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DOI：
10.1152/ajprenal.2000.279.5.f841
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发表时间：
2000-11-01
影响因子：
4.2
通讯作者：
Chappell, MC
中科院分区：
文献类型：
--
作者：
Allred, AJ;Diz, DI;Chappell, MC
血管紧张素(ANG)-(1-7)的两个主要作用部位是脉管系统和肾脏。由于关于这些组织中ANG-(1-7)代谢的信息很少，我们研究了大鼠肺和肾刷边膜（BBM）制剂中ANG-(1-7)肽的水解。放射性标记的ANG-(1-7)主要通过肺膜水解成ANG-(1-5)。ANG转换酶（ACE）抑制剂赖诺普利可以抑制ANG的生成（1-5），也可以抑制较小代谢产物的生成。体细胞（肺）和生发（睾丸）形式的大鼠ACE将ANG-(1-7)水解为ANG-(1-5)的动力学研究得出了相似的结果，表明cooh结构域负责ANG-(1-7)的水解。ANG-(1-5)的肺代谢产生ANG-(3-5)，与ACE无关，但可能涉及肽基或二肽基氨基肽酶。在肾皮质BBM中，ANG-(1-7)被迅速水解为单肽和二肽片段和ANG-(1-4)。氨基肽酶（AP）抑制减弱了ANG-(1-7)的水解，增加了ANG-(1-4)的形成。AP和neprilysin （Nep）抑制剂联合治疗可消除ANG-(1-4)的形成，并保留ANG-(1-7)。ACE抑制对BBM的水解速率和代谢产物形成没有影响。总之，ACE是肺中ANG-(1-7)代谢的主要酶活性，这与ACE抑制剂增加循环ANG-(1-7)半衰期和提高内源性肽水平的能力是一致的。在肾皮质发现了另一种代谢途径，相对于ACE活性，AP和Nep活性的增加促进ANG-(1-7)向ANG-(1-4)和更小片段的转化。
Two of the primary sites of actions for angiotensin (ANG)-(1-7) are the vasculature and the kidney. Because little information exists concerning the metabolism of ANG-(1-7) in these tissues, we investigated the hydrolysis of the peptide in rat lung and renal brush-border membrane (BBM) preparations. Radiolabeled ANG-(1-7) was hydrolyzed primarily to ANG-(1-5) by pulmonary membranes. The ANG-converting enzyme (ACE) inhibitor lisinopril abolished the generation of ANG( 1-5), as well as that of smaller metabolites. Kinetic studies of the hydrolysis of ANG-(1-7) to ANG-(1-5) by somatic (pulmonary) and germinal (testes) forms of rat ACE yielded similar values, suggesting that the COOH-domain is responsible for the hydrolysis of ANG-(1-7). Pulmonary metabolism of ANG-(1-5) yielded ANG-(3-5) and was independent of ACE but may involve peptidyl or dipeptidyl aminopeptidases. In renal cortex BBM, ANG-(1-7) was rapidly hydrolyzed to mono- and dipeptide fragments and ANG-(1-4). Aminopeptidase (AP) inhibition attenuated the hydrolysis of ANG-(1-7) and increased ANG-(1-4) formation. Combined treatment with AP and neprilysin (Nep) inhibitors abolished ANG-(1-4) formation and preserved ANG-(1-7). ACE inhibition had no effect on the rate of hydrolysis or the metabolites formed in the BBM. In conclusion, ACE was the major enzymatic activity responsible for the metabolism of ANG-(1-7) in the lung, which is consistent with the ability of ACE inhibitors to increase the half-life of circulating ANG-(1-7) and raise endogenous levels of the peptide. An alternate pathway of metabolism was revealed in the renal cortex, where increased AP and Nep activities, relative to ACE activity, promote conversion of ANG-(1-7) to ANG-(1-4) and smaller fragments.