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Clinical Relevance of Novel Angiotensin II Generation Pathway within the Kidney

肾脏内新型血管紧张素 II 生成途径的临床相关性

基本信息

批准号：
09470240
负责人：
SARUTA Takao
金额：
$ 4.16万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470240/
关键词：
chymase angiotensin kidney afferent arterioles efferent arterioles renal hemodynamics dexamethasone microscopy

项目摘要

Although angiotensin converting enzyme (ACE) inhibitors retard the progression of renal diseases, it remains undetermined whether a non-ACE-mediated pathway contributes to the angiotensin (ANG) ii generation within the kidney This study attempted to clarify the role of ACE and non-ACE pathway, including chymase, for ANG II generation within the kidney. ANG II generation via ACE-mediated and non-ACE-mediated pathways was examined. The ratio of ACE/non-ACE-mediated ANG II generation was 8 : 2 in dog renal cortex, whereas in the heart this value proved to be 4 : 6. In the kidney, when compared with the effects of intrarenally administered ANG I and [Pro^<11>, D-Ala^<12>]-ANG I (S) (an ANG I analog that cannot be converted to ANG II by ACE) on systemic blood pressure (BP) and renal blood flow (RBF), S required 100-fold higher concentrations to obtain the same degree of changes in BP and RBF.Further studies using intravital needle-type CCD camera microscopy demonstrated that renal afferent and efferent arteriolar actions of S were diminished, compared with those of ANG I.S at a dose of 100 nmol caused 30% decrements in RBF, which was completely abolished by an ANG receptor antagonist, but was only 50% inhibited by chymostatin. Finally, unlike systemic vascular beds, dexamethasone dilates the renal vasculature, which is associated with a decrease in renal interstitial ANG II formation and the paralleled inhibition of renal ACE activity, suggesting glucocorticoid does not affect non-ACE-mediated ANG II generation. Collectively, non-ACE activity, compared with ACE activity, contributes less to the renal ANG II generation, and chymase-mediated ANG II generation shares only half of the non-ACE-mediated ANG II production. Furthermore, non-ACE pathway does not play an important role in ANG II formation in glucocorticoid-treated kidneys Nevertheless, further studies are required to establish the role of non-ACE-mediated renal ANG II formation under a variety of renal diseases.

虽然血管紧张素转换酶（ACE）抑制剂可延缓肾脏疾病的进展，但非ACE介导的途径是否有助于肾脏内血管紧张素（ANG）II的生成仍不确定。本研究试图阐明ACE和非ACE途径（包括糜酶）在肾脏内ANG II生成中的作用。通过ACE介导的和非ACE介导的途径生成ANG II进行了检查。ACE/非ACE介导的ANG II生成的比率在犬肾皮质中为8：2，而在心脏中该值被证明为4：6。在肾脏中，当与肾内施用ANG I和[Pro^<11>，D-Ala^<12>]-ANG I（S）的作用相比时，（一种不能被ACE转化为ANG II的ANG I类似物）对全身血压（BP）和肾血流量（RBF）的影响，S需要100倍的高浓度才能获得相同程度的BP和RBF变化。使用活体针型CCD照相显微镜的进一步研究表明，S的肾传入和传出小动脉作用减弱，与ANG I相比，100 nmol的S可使RBF下降30%，而ANG受体拮抗剂可完全消除这种作用，而糜蛋白酶抑制剂仅抑制50%。最后，与全身血管床不同，地塞米松扩张肾血管，这与肾间质ANG II形成减少和肾ACE活性的抑制有关，表明糖皮质激素不影响非ACE介导的ANG II生成。总的来说，与ACE活性相比，非ACE活性对肾脏ANG II生成的贡献较小，并且糜酶介导的ANG II生成仅占非ACE介导的ANG II生成的一半。此外，在糖皮质激素治疗的肾脏中，非ACE途径在ANG II形成中不起重要作用。然而，需要进一步研究来确定非ACE介导的肾脏ANG II形成在各种肾脏疾病中的作用。