dushyant By Dushyant Kshatriya, Ph.D. .

The COVID-19 pandemic has caused millions of deaths worldwide and caused significant impact on the global economy. The risk of severe coronavirus disease 2019 (COVID-19) is higher in people with diabetes and obesity. The exact mechanism by which obesity and diabetes contribute to the pathophysiology of COVID-19 is unknown and one of the key player is believed to be related to the renin-angiotensin system (RAS).

图片

Fig 1. SARS-CoV-2 Spike Glycoprotein (S) and its potential role in viral infection to the host cell1

The SARS-CoV-2 virus impacts the respiratory system. The virus comprises a viral spike (S) protein that helps it attach and enter cells. It is known to be dependent on the angiotensin converting enzyme 2 (ACE2) of the host cell to gain entry into the cell. This process also utilizes the type II transmembrane serine protease (TMPRSS2) that cleaves and primes the viral spike protein for entry into the cell.

Aged individuals with diabetes are often prescribed RAS (Renin Angiotension System) blockers to prevent kidney failure. RAS blockers such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are primarily used to treat hypertension and other cardiovascular diseases to prevent heart/kidney failure or reduce the risk of stroke. It has been speculated that RAS blockers may increase COVID-19 by increasing ACE2 (See Figure 2). Two groups have studied the effects of metabolic disease such as diet induced obesity and diabetes on expression of ACE2, TMPRSS2, and RAAS enzymes in order to understand this further.

图片

Fig 2. The renin–angiotensin system (RAS) and the potential role of SARS-CoV-2 Spike Glycoprotein (S) in viral infection to the host cell, the stop signs stand for the targets where therapy options such as ACEi and ARB act upon2。This figure is adapted from Silhol et al 2020. 

Da Eira et al. 2021 showed that mice fed a 60 kcal% fat diet for sixteen weeks had higher expression of ACE2 and TMPRSS2 proteins in their lungs, but not in heart tissue, when compared with control diet and ketogenic diet fed animals3. In addition, the ketogenic diet exerted an anti-inflammatory response by reducing the expression of toll-like receptor 4, interleukin-6 receptor and tumor necrosis factor alpha. Angiotensin 1 and 2 receptors were found to be unchanged by the dietary interventions. ACE2 expression is thought to be increased to counteract the effect of the hyperactive ACE1/Ang-II/AT1R arm of the RAS system as seen in high-fat fed animals but not in the ketogenic-diet fed animals.

图片

Fig 3. Phenotype result of the animals at the control, high-fat, and ketogenic diets.

图片

Fig 4. The expression level of proteins ACE2 and TMPRSS2 at lungs。

图片

Fig 5. The expression level of inflammation markers at the lungs.

Batchu et al. 2021 showed that ACE2 and TMPRSS2 protein levels were higher in the lungs of STZ-induced-diabetic high-fat fed mice than in age-matched controls4. RAS blocking drugs such as Ramipril or telmisartan did not affect ACE2 or TMPRSS2 expression in the lungs of young or aged diabetic mice. This suggests that the upregulation of these genes is driven by comorbidity and is not increased further due to the use of RAS blocking drugs (See Figure 2).

图片

Fig 6. The plasma contents and the blood pressure of animals in each group. 

图片

Fig 7. The expression levels of protein - ACE2 and TMPRSS2 in the lung tissues of the control group and the Ramipril- and Telmisartan-treated groups.

To better represent what diets and formulas are used in these two teams, Dr. Kshatriya collected the relevant information and tabulates the table below.  

Formula Number Authors Diet Description
D12492 Da Eira et al. 2021 Rodent Diet With 60 kcal% Fat
D03022101 Da Eira et al. 2021 Rodent Diet With Nearly 0 kcal% Carbohydrate, 20 kcal% Protein and 80 kcal% Fat
D12451 Batchu et al. 2021 Rodent Diet With 45 kcal% Fat

Modified purified ingredient diets can be used to study various metabolic phenotypes and their impact on severity of COVID-19 infection. This will provide insights into the fundamental mechanisms that increase disease risk in certain populations.

Reference:

  1. Costa LB, Perez LG, Palmeira VA, Macedo E Cordeiro T, Ribeiro VT, Lanza K, Simões E Silva AC. Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System. Front Cell Dev Biol. 2020 Sep 16;8:559841. doi: 10.3389/fcell.2020.559841. PMID: 33042994; PMCID: PMC7525006.

  2. Silhol, F., Sarlon, G., Deharo, JC. et al. Downregulation of ACE2 induces overstimulation of the renin–angiotensin system in COVID-19: should we block the renin–angiotensin system?. Hypertens Res 43, 854–856 (2020). https://doi.org/10.1038/s41440-020-0476-3

  3. Da Eira D, Jani S, Ceddia RB. Obesogenic and Ketogenic Diets Distinctly Regulate the SARS-CoV-2 Entry Proteins ACE2 and TMPRSS2 and the Renin-Angiotensin System in Rat Lung and Heart Tissues. Nutrients. 2021 Sep 25;13(10):3357. doi: 10.3390/nu13103357. PMID: 34684358; PMCID: PMC8541329.

  4. 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 Sri Nagarjun Batchu, Harmandeep Kaur, Veera Ganesh Yerra, Suzanne L. Advani, M. Golam Kabir, Youan Liu, Thomas Klein, Andrew Advani Diabetes Mar 2021, 70 (3) 759-771; DOI: 10.2337/db20-0765