Plasma and Kidney Angiotensin Peptides: Importance of the Aminopeptidase A/Angiotensin III Axis.
Plasma and Kidney Angiotensin Peptides: Importance of the Aminopeptidase A/Angiotensin III Axis.
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DOI：
10.1093/ajh/hpv054
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发表时间：
2015-12
影响因子：
3.2
通讯作者：
J. Wysocki;M. Ye;D. Batlle
中科院分区：
文献类型：
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作者：
J. Wysocki;M. Ye;D. Batlle
背景：肾素-血管紧张素系统是一个复杂的调节性激素网络，其主要生物学肽和治疗靶点为血管紧张素II（Ang）（1-8）。还有其他潜在的重要的血管紧张素肽尚未得到很好的评价。方法采用液相色谱-串联质谱法（LC-MS/MS）对野生型（WT）小鼠肾脏和血浆中Ang I（1-10）和Ang II（1-8）下游的多种Ang进行同时检测。血管紧张素转化酶2敲除（ACE 2KO）也被用作在不存在ACE 2（一种切割Ang I（1-10）和Ang II（1-8）的酶）的情况下检查Angs谱的方法。结果在WT和ACE 2KO的血浆中，Ang I（1-10）、Ang III（2-8）和Ang（2-10）的水平在所有的RAS肽中是最高的。后两种肽分别是Ang II（1-8）和Ang I（1-10）的氨肽酶A裂解产物。相比之下，Ang II（1-8）和Ang（1-7）（ACE 2切割Ang II（1-8）的产物）的血浆水平较低。在WT和ACE 2KO的肾脏中，Ang II（1-8）水平高于血浆水平。在ACE 2KO小鼠中，在血浆或肾脏中未观察到Ang II（1-8）的显著增加或Ang（1-7）的减少。结论RAS聚焦肽组法显示小鼠血浆和肾脏中的Ang肽存在显著差异。这些Ang肽谱显示了在ACE 2/Ang（1-7）轴上的Ang I（1-10）和Ang II（1-8）代谢中氨肽酶A/Ang（2-10）和氨肽酶A/Ang III（2-8）途径的优势。Ang III（2-8）和其他由氨肽酶A裂解形成的肽可能是重要的治疗RAS靶点。
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. CONCLUSION 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.