The relationship between renin‐angiotensin system (RAS) and coronavirus disease 2019 (COVID‐19) pandemic and, in particular, RAS as part of the coronavirus 2 (CoV‐2) infection process via angiotensin‐converting enzyme 2 (ACE2), the entry point of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has resulted in conflicting suggestions regarding how RAS and its role(s) should inform treating COVID‐19. ACE inhibitors or angiotensin II (Ang)‐type 1 receptor blockers (ARBs), in fact, have been suggested to be avoided as they potentially upregulate ACE21 and, conversely, there are suggestions that ARBs might be beneficial2 as SARS‐CoV‐2 causing ACE2 downregulation slows the Ang II conversion to the vasodilatory, anti‐inflammatory, antioxidant and antiatherosclerotic Ang 1‐7,3-5 and the use of ARBs by blocking the excessive Ang II type‐1 receptors activation, would be beneficial upregulating ACE2 activity and increasing Ang 1 to 7 levels.

We have read with great interest the very recently published article by Cheng and coworkers,6 who reviewed the correlation between severe risk factors for COVID‐19 and ACE2. Their review highlighted the potential protective role of ACE2 in SARS‐CoV‐2 infection‐induced acute respiratory distress syndrome, the major cause of COVID‐19 mortality as well as other risk factors such as hypertension, diabetes, and cardiovascular disease that are linked to COVID‐19 morbidity and mortality.

We feel that our studies in Bartter's and Gitelman's syndrome patients (rare genetic tubulopathies) to explore and better define the human RAS system7 provide further insight on the protective effects of ACE2 in humans including the effects on prognosis of COVID‐19. Specifically, these patients have an activated RAS and high Ang II levels, yet blunted Ang II‐mediated cardiovascular effects and normotension or hypotension, activation of antiatherosclerotic and anti‐inflammatory defenses, reduced oxidative stress7 and, directly relevant to the discussion regarding ACE2, they have increased and correlated levels of both ACE2 and Ang 1‐7,8 therefore, a prevalence of the counterregulatory ACE2‐Ang 1‐7‐MasR axis over the classical ACE‐Ang II‐AT1R regulatory axis of RAS.9 These data suggest that increasing ACE2 via ARBs and ACE inhibitors might be beneficial via effects on Ang 1‐7 for patients infected by SARS‐CoV‐2 as this has been shown for ACE2 in hyperoxic lung injury.10

Moreover, our cohort of Gitelman's and Bartter's patients provides evidence, admittedly anecdotal, and circumstantial, allaying the concerns raised that increased ACE2 might provide more targets for the CoV‐2 virus. A telephone survey of over 100 of our Gitelman's and Bartter's patients, all from the Northern Italy Regions Veneto, Lombardia and Emilia Romagna, the hotspots of the COVID‐19 pandemic in Italy, found none of them infected with COVID‐19, making increased risk to COVID‐19 due to increased ACE2 unlikely.11

Finally, the increased and correlated levels of both ACE2 and Ang 1‐7 noted in Gitelman's and Bartter's patients also add support to Cheng and coworkers,6 suggestion that drugs enhancing ACE2 activity may become one of the most promising approaches for the treatment of COVID‐19 in the future.

肾素-血管紧张素系统 (RAS) 与 2019 年冠状病毒病 (COVID-19) 大流行之间的关系，特别是 RAS 作为冠状病毒 2 (CoV-2) 感染过程的一部分，通过血管紧张素转换酶 2 (ACE2)、严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的切入点，导致关于 RAS 及其作用应如何指导治疗 COVID-19 的建议相互矛盾。事实上，ACE 抑制剂或血管紧张素 II (Ang) 1 型受体阻滞剂 (ARB) 已被建议避免使用，因为它们可能会上调 ACE2 1，相反，有人建议 ARB 可能有益2作为 SARS-CoV- 2 引起 ACE2 下调会减缓 Ang II 向血管扩张、抗炎、抗氧化和抗动脉粥样硬化的 Ang 1-7 的转化，3-5和通过阻断过度的 Ang II type-1 受体激活来使用 ARB，将有利于上调 ACE2 活性并增加 Ang 1 至 7 的水平。

我们怀着极大的兴趣阅读了 Cheng 及其同事6最近发表的文章，他们回顾了 COVID-19 的严重危险因素与 ACE2 之间的相关性。他们的综述强调了 ACE2 在 SARS-CoV-2 感染引起的急性呼吸窘迫综合征中的潜在保护作用，这是导致 COVID-19 死亡的主要原因，以及与高血压、糖尿病和心血管疾病等其他风险因素相关的风险因素。 COVID-19 发病率和死亡率。

我们认为，我们对 Bartter 和 Gitelman 综合征患者（罕见的遗传性肾小管病变）的研究旨在探索和更好地定义人类 RAS 系统7，从而进一步了解 ACE2 对人类的保护作用，包括对 COVID-19 预后的影响。具体而言，这些患者具有激活的 RAS 和高 Ang II 水平，但减弱了 Ang II 介导的心血管作用和正常血压或低血压，激活了抗动脉粥样硬化和抗炎防御，减少了氧化应激7并且与关于 ACE2 的讨论直接相关，他们增加了 ACE2 和 Ang 1-7、8 的相关水平因此，反调节 ACE2-Ang 1-7-MasR 轴比 RAS 的经典 ACE-Ang II-AT1R 调节轴更普遍。9这些数据表明，对于感染 SARS-CoV-2 的患者，通过 ARB 和 ACE 抑制剂增加 ACE2 可能对 Ang 1-7 有益，因为这已在高氧性肺损伤中的 ACE2 中得到证实。10

此外，我们的 Gitelman 和 Bartter 患者队列提供了公认的轶事和间接证据，减轻了人们对 ACE2 增加可能为 CoV-2 病毒提供更多靶点的担忧。对来自意大利北部威尼托大区、伦巴第大区和艾米利亚罗马涅大区（意大利 COVID-19 大流行的热点地区）的 100 多名 Gitelman 和 Bartter 患者进行了电话调查，发现他们均未感染 COVID-19，从而增加了风险由于 ACE2 的增加不太可能导致 COVID-19。11

最后，在 Gitelman 和 Bartter 的患者中注意到的 ACE2 和 Ang 1-7 水平的增加和相关水平也增加了 Cheng 和同事的支持，6表明增强 ACE2 活性的药物可能成为治疗 COVID-1 最有希望的方法之一。未来19个。