Angiotensin converting enzyme‐2 (ACE‐2) is the cell‐surface receptor enabling viral uptake of corona virus 2019 (SARS‐CoV‐2), thus ACE‐2 is a first step towards COVID‐19 disease. ACE‐2 is a metalloenzyme located primarily on the apical surface, and serves as the entry point also for other coronaviruses, including HCoV‐NL63 and SARS‐CoV. Throughout evolution, ACE‐2 precedes renin, suggesting that ACE‐2’s role changed over time.¹

The renin angiotensin system (RAS) and COVID‐19 are intertwined.² Thus, various concerns come up regarding the safety of angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) for COVID‐19 patients. Interestingly, analogous concerns have not been raised for the Middle‐East Respiratory Syndrome (MERS), although MERS is also caused by a corona virus that is incorporated into cells, yet not by ACE‐2, but by dipeptidyl peptidase‐4.³

Novel coronavirus pneumonia is a new type of infectious disease, caused by SARS‐CoV‐2. The lungs are the first and primarily affected target organs of SARS‐CoV‐2. After infecting the lungs, the infiltrating viruses may enter the circulation and reach the kidneys, where they can accumulate and damage resident cells.⁴ Impaired glomerular filtration also occurs, usually manifested by increased blood creatinine and urea nitrogen levels, and moderate proteinuria. The incidence of reported acute kidney injury varies widely because of the different populations included in different studies, and is approximately 0.1%‐29%. High expression of ACE‐2 in the kidney, especially in podocytes and proximal tubular epithelial cells, may be related to the susceptibility of renal parenchymal cells and direct viral invasion of the renal parenchyma after COVID‐19 infection. However, in fact live virus have not been recovered from urine and viral mRNA has not been amplified from kidney biopsies.

Under physiological conditions, ACE‐2 converts ANGII to angiotensin (1‐7). Angiotensin (1‐7) changes the balance from ANGII‐induced vasoconstriction to Mas receptor‐activated vasodilation after extensive binding to Mas receptors. In addition, activation of the angiotensin (1‐7)/ACE‐2 axis inhibits the production of reactive oxygen species and downregulates secretion of pro‐inflammatory cytokines. Accordingly, binding of SARS‐CoV‐2 to ACE‐2 may weaken the activity of the latter and shift ACE/ACE‐2 balance to a state of enhanced ANGII activity, which leads to vasoconstriction and inflammatory⁵ and oxidative organ damage, and further promotes damage.⁶

The use of RAS inhibitors can increase expression of ACE‐2 on the tissue and apical surface to a certain extent. Therefore, the use of ACEIs or ARBs to treat diseases is considered likely to increase the risk of SARS‐CoV‐2 exposure. However, so far, there is no experimental evidence indicating that ACEIs or ARBs augment the susceptibility to SARS‐CoV‐2 or aggravate the outcomes and severity of COVID‐19. Accordingly, large observational studies have not shown any association with increased COVID‐19 risk and patients who are receiving ACE inhibitors or ARBs.⁷

After SARS‐CoV infection in mice, ACE‐2 protein levels are greatly reduced, depending on virus replication, which is consistent with the situation in host cells.⁸ Additionally, SARS‐CoV‐2 can weaken the activity of ACE‐2 by binding to ACE‐2. In consequence, elevated ANGII further aggravates kidney injury by activating AT₁R, causing inflammation and fibrosis. Inhibiting RAS by ACEIs/ARBs or recombinant ACE‐2 increases expression of ACE‐2, thereby reducing ANGII levels and enhancing Ang‐(1‐7) generation. Increased ACE‐2 expression promotes the activation of Mas receptor (MasR), which in turn attenuates inflammation and fibrosis, and therefore attenuates kidney injury.⁹ Moreover, the increase in the level of soluble ACE‐2 may also neutralize SARS‐CoV‐2, limit virus entry and reduce tissue damage. Therefore, providing RAS inhibitors seems advantageous for COVID‐19 patients (Figure 1A). Indeed, observational cohort studies, and randomized trials for other endpoints provide no evidence for adverse effects RAS inhibition in COVID‐19.⁷ Thus, RAS inhibitors should not be withheld from patients because of any SARS‐CoV‐2 concerns.^{10, 11} The contrary may hold true.

Monteil et al¹² reported that infection with SARS‐CoV‐2 can be inhibited with a human recombinant soluble ACE‐2 (hrsACE‐2). The hrsACE‐2 reduced SARS‐CoV‐2 recovery from Vero cells by a factor of 1000‐5000. The investigators also showed that SARS‐CoV‐2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE‐2. Other sophisticated approaches are suggested by Chan et al¹³ By using deep mutagenesis, that group identified mutations in ACE‐2 that increased spike protein binding across the interaction surface, in the asparagine 90‐glycosylation motif, and at buried sites. The mutational landscape provided the group with a blueprint for understanding the specificity of the interaction between ACE‐2 and spike protein, as well as for engineering high‐affinity decoy receptors. Combining mutations brought up ACE‐2 variants affinities that rival those of monoclonal antibodies. A stable dimeric variant reveals potent SARS‐CoV‐2 and SARS‐CoV neutralization in vitro. The engineered soluble ACE‐2 receptor was catalytically active, and its close similarity with the native receptor could limit the potential for viral escape (Figure 1B). These novel approaches could help us therapeutically in the future.

血管紧张素转换酶-2 (ACE-2) 是细胞表面受体，能够使病毒摄取 2019 年冠状病毒 (SARS-CoV-2)，因此 ACE-2 是迈向 COVID-19 疾病的第一步。ACE-2 是一种主要位于顶端表面的金属酶，也是其他冠状病毒的入口点，包括 HCoV-NL63 和 SARS-CoV。在整个进化过程中，ACE-2 先于肾素，这表明 ACE-2 的作用随着时间而改变。¹

肾素血管紧张素系统 (RAS) 和 COVID-19 相互交织。²因此，对于 COVID-19 患者的血管紧张素转换酶抑制剂 (ACEI) 和血管紧张素受体阻滞剂 (ARB) 的安全性，出现了各种担忧。有趣的是，中东呼吸综合征 (MERS) 并未引起类似的担忧，尽管 MERS 也是由掺入细胞的冠状病毒引起的，但不是由 ACE-2 引起的，而是由二肽基肽酶-4 引起的。³

新型冠状病毒肺炎是由SARS-CoV-2引起的一种新型传染病。肺是 SARS-CoV-2 的第一个也是主要受影响的靶器官。感染肺部后，浸润的病毒可能会进入循环系统并到达肾脏，在那里它们可以积累并破坏常驻细胞。⁴也会出现肾小球滤过受损，通常表现为血肌酐和尿素氮水平升高，以及中度蛋白尿。报告的急性肾损伤的发生率因不同研究中的人群不同而差异很大，约为 0.1%~29%。ACE-2在肾脏，尤其是足细胞和近端肾小管上皮细胞中的高表达，可能与COVID-19感染后肾实质细胞易感性和病毒直接侵入肾实质有关。然而，事实上，活病毒还没有从尿液中回收，病毒 mRNA 也没有从肾活检中扩增。

在生理条件下，ACE-2 将 ANGII 转化为血管紧张素 (1-7)。血管紧张素 (1-7) 在与 Mas 受体广泛结合后，将平衡从 ANGII 诱导的血管收缩转变为 Mas 受体激活的血管舒张。此外，血管紧张素 (1-7)/ACE-2 轴的激活可抑制活性氧的产生并下调促炎细胞因子的分泌。因此，SARS-CoV-2 与 ACE-2 的结合可能会削弱后者的活性，并将 ACE/ACE-2 平衡转变为 ANGII 活性增强的状态，从而导致血管收缩和炎症⁵和氧化器官损伤，并进一步促进损害。⁶

RAS抑制剂的使用可在一定程度上增加组织和根尖表面ACE-2的表达。因此，使用 ACEI 或 ARB 治疗疾病被认为可能会增加 SARS-CoV-2 暴露的风险。然而，到目前为止，没有实验证据表明 ACEI 或 ARB 会增加对 SARS-CoV-2 的易感性或加重 COVID-19 的结果和严重程度。因此，大型观察性研究未显示与 COVID-19 风险增加和正在接受 ACE 抑制剂或 ARB 的患者有任何关联。⁷

小鼠感染SARS-CoV后，ACE-2蛋白水平大大降低，这取决于病毒的复制，这与宿主细胞的情况是一致的。⁸此外，SARS-CoV-2 可以通过与 ACE-2 结合来削弱 ACE-2 的活性。因此，升高的 ANGII 通过激活 AT ₁ R 进一步加重肾损伤，引起炎症和纤维化。通过 ACEI/ARB 或重组 ACE-2 抑制 RAS 会增加 ACE-2 的表达，从而降低 ANGII 水平并增强 Ang-(1-7) 的生成。ACE-2 表达的增加促进了 Mas 受体 (MasR) 的激活，从而减轻炎症和纤维化，从而减轻肾损伤。⁹此外，可溶性 ACE-2 水平的增加还可以中和 SARS-CoV-2，限制病毒进入并减少组织损伤。因此，提供 RAS 抑制剂似乎对 COVID-19 患者有利（图 1A）。事实上，观察性队列研究和其他终点的随机试验没有提供证据表明 RAS 抑制对 COVID-19 有不利影响。⁷因此，不应出于对 SARS-CoV-2 的任何担忧而对患者停用 RAS 抑制剂。^{10, 11}可能恰恰相反。

Monteil 等人¹²报道，人类重组可溶性 ACE-2 (hrsACE-2) 可以抑制 SARS-CoV-2 感染。hrsACE-2 将 Vero 细胞的 SARS-CoV-2 回收率降低了 1000-5000 倍。研究人员还表明，SARS-CoV-2 可以直接感染工程化的人体血管类器官和人体肾脏类器官，而 hrsACE-2 可以抑制这些器官。Chan 等人提出了其他复杂的方法¹³通过使用深度诱变，该小组确定了 ACE-2 中的突变，这些突变增加了跨相互作用表面、天冬酰胺 90-糖基化基序和隐藏位点的刺突蛋白结合。突变景观为该小组提供了了解 ACE-2 和刺突蛋白之间相互作用的特异性以及设计高亲和力诱饵受体的蓝图。结合突变产生了与单克隆抗体相媲美的 ACE-2 变体亲和力。一种稳定的二聚体变体在体外显示出有效的 SARS-CoV-2 和 SARS-CoV 中和作用。工程改造的可溶性 ACE-2 受体具有催化活性，它与天然受体的密切相似性可以限制病毒逃逸的可能性（图 1B）。这些新方法可以在未来帮助我们进行治疗。