Lung and Kidney ACE2 and TMPRSS2 in Renin-Angiotensin System Blocker-Treated Comorbid Diabetic Mice Mimicking Host Factors That Have Been Linked to Severe COVID-19
Lung and Kidney ACE2 and TMPRSS2 in Renin-Angiotensin System Blocker-Treated Comorbid Diabetic Mice Mimicking Host Factors That Have Been Linked to Severe COVID-19
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DOI：
10.2337/db20-0765
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发表时间：
2021-03-01
期刊：
影响因子：
7.7
通讯作者：
Advani, Andrew
中科院分区：
文献类型：
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作者：
Batchu, Sri Nagarjun;Kaur, Harmandeep;Advani, Andrew
糖尿病患者患 2019 年严重冠状病毒病 (COVID-19) 的风险增加的原因尚不清楚。据推测，肾素血管紧张素系统 (RAS) 阻滞剂可能通过增加 ACE2 以及宿主蛋白酶 TMPRSS2 来促进 COVID-19，严重急性呼吸综合征冠状病毒 2 利用 ACE2 进入宿主细胞。我们采用逆翻译方法，结合原位杂交、原代细胞分离、免疫印迹、定量 RT-PCR 和液相色谱-串联质谱法，研究了糖尿病小鼠的肺和肾 ACE2 和 TMPRSS2，模拟了与严重 COVID-19 相关的宿主因子。在健康的年轻小鼠中，ACE 抑制剂雷米普利和 AT1 受体阻滞剂替米沙坦均不影响肺或肾 ACE2 或 TMPRSS2，只是雷米普利使肾脏 ACE2 蛋白小幅增加。相比之下，患有糖尿病（衰老、高脂肪饮食和链脲佐菌素诱导的糖尿病）的小鼠肺 ACE2 和 TMPRSS2 蛋白水平升高，肺 ACE2 活性增加。这些参数均不受 RAS 封锁的影响。与老年对照相比，患有糖尿病的小鼠的肾脏中 ACE2 的表达同样上调，而 TMPRSS2（主要是远端肾单位）在替米沙坦治疗的动物中表达最高。合并糖尿病时肺 ACE2 活性的上调可能会导致严重 COVID-19 的风险增加。这种上调是由合并症而非 RAS 阻断驱动的。
The causes of the increased risk of severe coronavirus disease 2019 (COVID-19) in people with diabetes are unclear. It has been speculated that renin-angiotensin system (RAS) blockers may promote COVID-19 by increasing ACE2, which severe acute respiratory syndrome coronavirus 2 uses to enter host cells, along with the host protease TMPRSS2. Taking a reverse translational approach and by combining in situ hybridization, primary cell isolation, immunoblotting, quantitative RT-PCR, and liquid chromatography-tandem mass spectrometry, we studied lung and kidney ACE2 and TMPRSS2 in diabetic mice mimicking host factors linked to severe COVID-19. In healthy young mice, neither the ACE inhibitor ramipril nor the AT1 receptor blocker telmisartan affected lung or kidney ACE2 or TMPRSS2, except for a small increase in kidney ACE2 protein with ramipril. In contrast, mice with comorbid diabetes (aging, high-fat diet, and streptozotocin-induced diabetes) had heightened lung ACE2 and TMPRSS2 protein levels and increased lung ACE2 activity. None of these parameters were affected by RAS blockade. ACE2 was similarly upregulated in the kidneys of mice with comorbid diabetes compared with aged controls, whereas TMPRSS2 (primarily distal nephron) was highest in telmisartan-treated animals. Upregulation of lung ACE2 activity in comorbid diabetes may contribute to an increased risk of severe COVID-19. This upregulation is driven by comorbidity and not by RAS blockade.