Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.).
Pharmacol Rev. 2022 Jul;74(3):462-505. doi: 10.1124/pharmrev.120.000236.
The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.
过去 10-15 年来，肾局部形成血管紧张素 II 的概念发生了变化。人们提出了近端肾小管中血管紧张素原的局部合成，结合了集合管中前肾素的合成。通过所谓的（前）肾素受体结合、以及巨球蛋白介导的过滤后血浆来源肾素-血管紧张素系统（RAS）成分的摄取，引入了前肾素的结合。此外，除了血管紧张素 II 之外，还存在其他血管紧张素代谢物[特别是血管紧张素-(1-7)]，血管紧张素通过三种不同的受体发挥作用，其中血管紧张素 II 型 2 和 Mas 受体被认为具有肾保护作用，可能具有性别特异性，而血管紧张素 II 型 1（AT）受体被认为是有害的。此外，内化的血管紧张素 II 可能会刺激细胞内受体。血管紧张素转换酶 2（ACE2）不仅产生血管紧张素-(1-7)，还作为冠状病毒受体发挥作用。如果不是所有的心血管疾病都涉及肾 RAS，那么多种心血管疾病都涉及肾 RAS，肾 AT 受体通常被认为发挥着关键作用。根据过滤、重吸收和局部释放，尿 RAS 成分水平被认为反映了肾 RAS 的活性。最后，现有的药物（RAS 抑制剂、环氧化酶抑制剂）和新型药物（血管紧张素受体/脑啡肽酶抑制剂、钠-葡萄糖共转运蛋白-2 抑制剂、可溶性 ACE2）都影响肾血管紧张素的形成，从而显示出心血管疗效。特别是在后三种情况下，一个重要的问题是它们在多大程度上诱导了肾保护（例如，以肾 RAS 依赖性的方式）。这篇综述提供了一个统一的观点，不仅解释了肾血管紧张素形成的发生方式，以及药物如何影响肾血管紧张素的形成，还解释了为什么改变肾 RAS 时药物会具有肾保护作用。意义重大：肾血管紧张素的形成已被广泛接受，但知之甚少，在过去二十年中提出了多种相互矛盾的概念。本文提供了一个统一的观点，同时解释了现有和新型药物如何通过干扰肾血管紧张素的形成来发挥肾保护作用。
