Clinical Relevance of Novel Angiotensin II Generation Pathway within the Kidney

尽管血管紧张素转换酶（ACE）抑制剂延缓了肾脏疾病的进展，但仍不确定非ACE介导的途径是否有助于肾脏内血管紧张素（ANG） ii的生成。本研究试图阐明ACE和非ACE途径（包括酶）在肾脏内ANG ii生成中的作用。通过ace介导和非ace介导的途径检测ANG II的生成。在狗肾皮质，ACE/非ACE介导的ANG II生成的比例为8:2，而在心脏，这一比例为4:6。在肾脏中，与静脉给药ANG I和[Pro^<11>, D-Ala^<12>]-ANG I（一种不能通过ACE转化为ANG II的ANG I类似物）对全身血压（BP）和肾血流量（RBF）的影响相比，S需要高100倍的浓度才能获得相同程度的BP和RBF变化。进一步的研究表明，与angi相比，S的肾传入和输出小动脉作用减弱，100 nmol剂量的S引起RBF减少30%，ANG受体拮抗剂完全消除RBF，但凝血抑素仅抑制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形成的减少和肾ACE活性的平行抑制有关，表明糖皮质激素不影响非ACE介导的ANG II的生成。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，而乳糜介导的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形成中并不起重要作用。然而，在多种肾脏疾病中，非ace介导的肾脏ANG II形成的作用有待进一步研究。

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.