Vitamin D and ACE2

Stu asked me about the relationship between vitamin D and the ACE2 receptor. At the time I hadn’t given it much thought but the question was so interesting that it got me reading. What follows is my take on the issue based on what I’ve been able to learn.

For SARS-CoV2 to infect humans the virus has enter cells in order to replicate and produce more copies of itself. It has been determined that the viral entry point into cells in COVID-19 is angiotensin converting enzyme2 (ACE2)- the ACE2 receptor. ACE2 is embedded in the cellular membrane of many different cell types including those of the lungs and lining of blood vessels. Apparently the spike protein of the virus binds to ACE2 by interacting with the part of ACE2 that protrudes from cells (extracellular domain). After this binding occurs, the cell membrane changes shape and effectively swallows the virus and ACE2. Once the virus is inside our cells, it can use the cells’ synthetic machinery to make copies of itself, which can be released to infect more cells. In the context of this blog, I would like to address the existence of a relationship between vitamin D and ACE2.

Various observations have implicated vitamin D with control of the renin-angiotensin sytem (RAS), which is involved in the regulation of blood pressure. Briefly renin released by the kidney activates angiotensin, which can increase blood pressure. For this discussion, I ask you to accept that ACE2 is part of the RAS and changes in blood pressure can be related to changes in ACE2. An early observation associated blood pressure increases with the winter season, when vitamin D status in humans is poorest. Higher blood renin levels have been associated with lower vitamin D levels and vice-versa. Vitamin D treatment has been reported to decreased blood pressure in some studies. Thus, the seed has been planted for the notion that vitamin D might be involved in modifying the activity of ACE2.

In laboratory animal and cell experiments, it has been demonstrated that mice lacking vitamin D receptors had increased activity of RAS. The higher blood pressure of these mice was corrected by inhibitors of RAS. In cultured kidney cells, vitamin D decreased the formation of renin. Experimental observations like these are consistent with the idea that there are mechanisms by which vitamin D can regulate components of RAS. But what about ACE2 per se?

There doesn’t seem to be evidence that vitamin D can interact directly with ACE2, but there are reports that vitamin D has indirect effects. Accordingly vitamin D (calcitriol, 1,25 (OH)₂D) can increase the expression of ACE2. Moreover there are many treatments/conditions that can result in an increase in ACE2 protein. This would be expected to make cells more sensitive to infection by SARS-CoV2 by virtue of providing more entry receptors. On the other hand, increased ACE2 could increase the quantity of angiotensin(1-7) which is vasodilatory and anti-inflammatory and decrease the quantity of angiotensin(1-8) which is vasoconstrictor and pro-inflammatory. Conditions such as diabetes and hypertension are associated with decreased ACE2, and seem to increase the severity of COVID-19. This is further complicated by the possibility that the part of ACE2 to which the virus (SARS-CoV2) binds can be released from cells into the extracellular water (see below); this form of ACE2 can also bind the virus and therefore be protective. With multiple competing processes, it becomes difficult to provide a simple description of the interaction between vitamin D, ACE2 and COVID-19 severity. Nevertheless, the beneficial aspects of increased ACE2 appear to be greater than the negative aspects.

ACE2 is a 806 amino acid protein with an intracellular domain, trans-membrane segment and an extracellular domain. Its carboxypeptidase activity lies in the extracellular domain; it can convert angiotensin(1-8) to angiotensin(1-7), and angiotensin(1-10) to angiotensin(1-9). The extracellular enzymatically active domain can be released into the extracellular space by the action of sheddase. Once released it is still enzymatically active and can also bind SARS-CoV2. Various research groups are working on elucidating details of the steps where the virus binds to ACE2 and enters cells. As it is a multistep process, there are numerous opportunities to target individual steps in the search for drugs that will be able to combat SARS-CoV2 infection. It would be nice to have a drug that nullified all the spike protein binding sites and protected our susceptible cells. I look forward to seeing the results of research in this area.