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Pari Rapti, Endocrinologist

“Endocrine” RAS system and COVID-19

A hypothesis

By Pari Rapti, Endocrinologist

The unexpected appearance of the viral infection COVID-19, with tremendous global consequences, creates thoughts and concerns to doctors and researchers, regarding the possible impacts on other systems of the organism, such as the cardiovascular, gastrointestinal, the nervous, brain, the urinary genital and the endocrine systems.

Various research, conducted internationally, show that an interesting correlation seems to exist between the COVID-19 infection and particular metabolic pathways, and I believe in implication of endocrinological pathways and axis also. Those pathways are related to the existence of the ACE2 receptor, which is present  most ,on the alveolar epithelial cells of the lungs and to the receptor’s expression.

Additionally, a correlation seems to exist between COVID-19 and the action of particular substances produced in the case of an inflammation, named proinflammatory factors or cytokines, which in some COVID-19 cases occur in the form of a “cytokine storm”. We know that cytokines and especially Interleukin 6 (pleiotropic), are produced in various endocrine systems and glands throughout the organism, as well as in other organs, and regulate various biological procedures and responses, in each of the systems.

In the case of a coronavirus infection, those substances might contribute to the occurrence of a poly-systemic syndrome (in multiple organs), in potentially genetically predisposed patients.

A further examination of those endocrine and metabolic pathways might be important in examining the severity of the disease and in understanding, dealing and finding the disease severity markers, as well as in studying the genetic differences between the two sexes or between different populations.

We know that on the surface of the alveolar epithelial cells of the lung, which comprise the 15% of the lung cells, there are approximately 83% of the ACE2 (Angiotensin-converting enzyme 2) receptors, whereas the rest of them are located in other organs. These receptors are important for the function and regulation of the Renin–Angiotensin–Aldosterone System (RAAS).

In the COVID-19 infection, the ACE2 receptor, as it is reported in the international scientific literature, seems to be connected to the Spike (S) glycoprotein of the coronavirus, through the presence of a particular protease transmembrane to pneumonocyte II, and other cell, the serine protease TMPRSS2, ADAM17, cathepsin L.

The protease TMPRSS2 and the others, with different way, cleaves the Spike (S) glycoprotein of the coronavirus.  This is a necessary condition, in order for the virus to enter the host cell, where the virus’ RNA uses the infected cell’s substances and pathways to replicate itself, creating a large number of viruses that will infect other cells.

Moreover, there is a need to highlight the fact that Type II lung cells produce a surface-active substance, (pulmonary surfactant), which has immunoregulatory properties and prevents the collapse of the cells. The hypoxia created and its consequences in COVID-19 and the microenvironment pH should be taken into consideration.

In genetic predisposition of patients, the possible important role of the following procedure should be emphasized: As we mentioned earlier, ACE2 (Angiotensin-converting enzyme 2) receptors exist on the surface of the epithelial lung cells, which are related to the glycoprotein Spike (S) of the virus.

As a result of this complex, the virus enters the cytoplasm and the receptors ACE2 on the lung cells’ surface are reduced.  The ACE2 receptor is also a converter of the immune response.  The role of ACE2 is to convert Angiotensin I to Angiotensin II and Angiotensin (1-7).

The Angiotensin-Converting Enzyme 2 (ACE2 / the equivalent of the known ACE, which converts Ang I to Ang II) is an aminopeptidase.  Normally, ACE2 cleaves Angiotensin II (Ang II) to Angiotensin (1-7) and consequently converts Ang I to Ang (1-9).  Thus, through ACE2, vasodilatation is induced, and cardio-renal protection is accorded, through the reduction of Ang II levels and the parallel increase of the Ang (1-7) levels.  ACE2 receptors play a role in the pathogenesis of hypertension and diabetes mellitus, and they are expressed in the epithelial cells of many organs.

Angiotensin II is a peptide consisting of eight amino acids, which is formed with the assistance of the Angiotensin-Converting Enzyme (ACE) through the conversion of Angiotensin I.  Angiotensin II is further metabolized to Angiotensin III.  The release of Angiotensin II is regulated by renin, blood pressure, blood volume, sodium balance and the concentration of aldosterone.  Angiotensin II stimulates the release of the antidiuretic hormone (ADH), the adrenocorticotropic hormone (ACTH), the prolactin, the luteinizing hormone (LH), the oxytocin, the aldosterone and others.  Moreover, it increases vasoconstriction and defers the sodium reabsorption by the renal tubules and stimulates the development of the endothelial cells.

However, it is important that drugs, such as diuretics, mineralocorticoids, glucocorticoids, estrogens, oral contraceptives, adrenocorticotropic hormone, sodium, potassium, as well as the body posture during blood collection, influence Angiotensin II levels.  In COVID-19, the levels of Angiotensin II appear to increase.

All the implicated factors, which were mentioned above, are genetically defined and there is a high genetic diversity.

Two pathways are highly important inside the infected cell, JAK/STAT and NF-κB, and in the case of the coronavirus, the second pathway should be taken into consideration when dealing with the issues caused by the coronavirus.

Focus on the thoughts and replay some knowledge let’s think again

which is the relationship of ACE2 with Proteases, ADAM17, TMPRSS2, Cathepsin and the role of Angiotensin and Endocrinological pathways in COVID-19.

Since the beginnings of the 2020 pandemic, as a result of the great scientific interest but also the serious effects of the disease on health worldwide, my personal interest to understand the possible involvement of endocrinology in the development and severity of COVID-19, has led me to study and investigate the possible endocrinology-related mechanisms, as well as the possible involvement of endocrine and metabolic pathways in the new disease.

The presence and significance of how SARS-CoV-2 enters the body through the ACE2 receptor, which is of paramount importance as shown in the international literature of studies over the last 15 years, compels researchers to understand how this endocrine “receptor” functions and the role of RAS in every organism.

This receptor is an integral component of the renin-angiotensin-aldosterone system (RAAS)

with local RAS having many other biological functions in addition to the endocrine system’s, important role in homeostasis, as shown in recent years.

The ‘classical’ renin–angiotensin system (RAS) is a circulating system with important roles, but Local/paracrine RAS, also identified in a variety of tissues, and probably is involved in different functions and diseases

Another type of RAS (intracellular/intracrine RAS) has been observed in some types of cells, but their role is unknown.

Maybe one inappropriate activation of the renin-angiotensin system (RAS), provoke, vascular injury in vessels endothelium and in other different organ, with importance role of ACE (AT1, AT2) and ACE2 (MAS) and their axis, mand this in COVID-19 is interesting because of ACE2 decrease.

For example, Angiotensin II (Ang II) upregulates vascular endothelial growth factor (VEGF) and activates vascular inflammation, possible (Essential Role have Vascular Endothelial Growth Factor in Angiotensin II–Induced Vascular Inflammation).

ACE2 catalyzes the cleavage of ANG 1 into ANG (1-7). The biological effects of ANG (1-7) are impressive, as shown in international literature, therefore a reduction in the production of this ANG (1-7) in a COVID-19 setting, as a result of a reduction of the ACE2 receptor, which binds to the Spike (S) protein of SARS-CoV-2, is becoming an essential field for investigating the effects of reduced ANG (1-7) levels.

Another point that compels the study of the endocrine pathways’ involvement is that TMPRSS2, ADAM17, cathepsin, and other proteases which are necessary for the formation of the Spike (S)–ACE2 complex appear to be expressed in several ways by various hormones. In specific, TMPRSS2 is androgen dependent.

Consequently, hormonal and genetic factors could lead to ACE2 over-expression in female sex. For example, sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-estradiol-dependent and probably related with thyroxine level, and other hormones in the blood

The location of ACE2 is in chromosome X22.2.

ACE2 is attached to the cell membrane of enterocytes of the small intestine, duodenum, proximal tubular cells of kidneys, glandular cells of the gallbladder, Sertoli cells, Leydig cells of testis, endothelial cells, pericytes of vessels cardiomyocytes, thyroid gland, epididymis, seminal vesicle, pancreas, liver, placenta, respiratory system.

The ACE2 gene it maps to chromosome X at position Xp22.8.

ACE2 polymorphism is crucial in various diseases

the role of AT1R gene together with the ACE gene is crucial

TMPRSS2 is locate in chromosome 21q22

TRIM28 is found co-expressed with ACE2 and TMPRSS2 among type II pneumocytes, might play a role in potentiating an IFN response in lung epithelial cells.


About ANG (1-7)

Many questions have been raised in international literature and answers provided about this hormone’s mechanism. In this case, though, it is of great interest to investigate and document the potential of ANG (1-7) as an endogenous inhibitor of ANG-II’s pathological actions.

All organs expressing the ACE2 receptor should be further investigated, also separately, as to how their reduction in COVID-19 and the possible increase of ACEs, and consequently of ANG-II, may cause tissue damage.  Furthermore, the reduction of ACE2 and consequently the reduction of ANG (1-7)’s protective effect may augment the severity of the end damage caused by the action of ANG-II, and the reversal of this condition could possibly also reverse the clinical picture of patients.

The role of ANG (1-7) in the endocrine system

ANG (1-7) is one of the most active peptides of the renin-angiotensin system (RAS). Its action in cardiovascular systems is already known. The question is what the role of ANG (1-7) in the prevention of metabolic disorders could be, such as metabolic syndrome, obesity, diabetes, lipid disorders, glucose metabolism disorders and possible regulatory stimuli disorders of the hunger-satiety-thirst mechanism.

Questions that arise concern the effect of ANG (1-7) on the reproductive organs, such as the ovaries, testes, pancreas, and other endocrine glands, where ACE2 and MAS receptors are expressed.

RAS is known to be expressed in different tissues and cells, but also in different cell types. Although ANG (1-7) is a hormonal peptide that has been the subject of numerous research protocols aimed at documenting the biological effects of protective ANG (1-7), further investigation could potentially lead to new therapeutic strategies involving cardiovascular disorders, metabolic diseases, hypertension and COVID-19.

In the field of endocrinology research, there is much information on the actions of ANG (1-7), e.g., that the ACE2/ ANG (1-7)/ MAS axis is involved in the regulation of insulin, glucagon, phosphorylation of insulin-related proteins, ERK1/2 activation and protein kinase (PKC).

The same axis also appears to reduce oxidative stress in the pancreas, thus improving insulin secretion. Furthermore, ANG (1-7) is also expressed in the ovary and regulated by gonadotropins (hormones).

Many biological privileges of women against various pathologies may be due, among other things, to the estrogen-regulated expression and activity of ACE2, and this needs to be further investigated.

ANG (1-7) is also expressed in the human testis; it is abundant in the cytoplasm of LEYDIG cells, but also in the cytoplasm of SERTOLI cells, and in primary sperm. It is striking that ANG (1-7) reduces testosterone production.

Furthermore, the effect of ANG (1-7) on adipocytes seems to be very important. Adipocytes show significant activity in the synthesis of proinflammatory agents, chemotactic agents, the chemoattractant of prostaglandins, hormones, cytokines.

Lipokines, leptin, and other topically synthesized hormones modulate insulin sensitivity, insulin resistance, and this is important in metabolic syndrome, obesity, type 2 diabetes, and other metabolic disorders. Some researchers also point to the possible involvement of adiponectin.

The new COVID-19 disease has brought about, in addition to huge socio-economic problems, the need to understand viral contamination mechanisms and disease progression.

It is therefore a matter of priority to understand the molecular mechanisms involved in the pathophysiology of the disease, as well as the cellular functions and modifications that occur with infection, in order to understand the risk factors, to investigate and to clarify the possible genetic predisposition in connection to disease severity, to record biomarkers, both during and soon after recovery, and to understand the effectiveness of therapeutic approaches.

The triangle of interdependence between the ACE2 receptor spike and proteases should be studied and all possible interactions between the vertices of this triangle should be clarified, since they are critical and act as a “key” factor in disease progression.

Each factor that affects how RAS functions, and each genetic factor that concerns the expression of both proteases and RAS elements, may lead to a different expression of COVID-19 between different sexes, different ages, different races and population groups.

The involvement of ACE2, a renin-angiotensin converting enzyme receptor, which has an important role in RAS function, also works as a viral receptor in the case of COVID-19, allowing the virus to invade the host cytoplasm.

There is strong evidence in international literature that ACE2 and its expression are subject to regulatory, genetic, hormonal, age-related and other mechanisms.

In several cardiovascular and respiratory diseases, the expression of these receptors appears to be modified. The same is seen in other diseases, such as kidney disease and diabetes mellitus, where higher expression of ACE2 levels has been found, as well as increased protease activity, such as of ADAM17.

The Role of gene expression and transcriptional factors for Every single component, (ACE, AE2, AT1, AT2, MAS, ADAM17, TMPRSS2 maybe is truly decisive for the introduction infected in various cells of virus but also for the disease.

Research also shows that the role of its cleavage by ADAM17 or TMPRSS2 is important. It has also been reported that in SARS-CoV-2, where increased expression of Interleukin 1 beta occurs, an overactivity of ADAM17 is recorded at the early stages of infection.

Subsequently, the SARS-CoV-2 complex, with ADAM17-mediated regulation, may impair RAS function in certain cases. In short, the role of proteases is crucial.

Proteases, which play an important role in the cleavage of the Spike (S)-ACE2 complex, appear to function differently, and this may explain the different effects between sexes, ages and races.

Interesting observations in international literature have recorded a differentiated expression of TMPRSS2 in the nasal epithelium of different race individuals. Higher mortality rates have also been reported in individuals with specific comorbidities and of specific age, which affect the different mediated expression of proteases.

However, the factors involved are more complex, e.g., the pathway involving cathepsin L depends on the local microenvironment’s pH.

Furthermore, the transmembrane ACE2 receptor is found in the endothelial cells of various organs, and the gene that expresses it is polymorphic and expressed on the X chromosome. This raises the question of whether its expression and the activation of RAS is different between men and women, as well as what is the role of proteases and their different expression in different individuals. The expression of the ACE2 receptor is also affected by other factors, such as the lifestyle, age, and endocrine disorders, such as of the thyroid gland, as well as by habits such as smoking, perhaps through the alpha nicotinic receptor.

We may even refer to environmental factors, such as smog (air pollution) and others. Even a high-salt diet tends to affect the ACE-ACE2 ratio at kidney level. Glucose-rich foods may also affect this ratio by reducing ACE2.

As regards the ADAM17 protease, which is expressed in many tissues and endocrine organs, such as the ovaries, testes, pancreas, thymus gland, but also in other organs such as the heart, lungs, kidneys, small intestine, the study should be more extensive, since its expression appears to be affected by various factors, such as fibroblast growth factor (FGF7), activators of protein kinase C (PKC), purine receptor 2 (P2) agonists, but also in response to infections through toll-type receptors. Nonetheless, the action of ADAM17 is associated with the soluble active form of TNfa and the epidermal growth factor receptor (EGFR).

Finally, the configuration of the ADAM17 and EGFR receptor axis needs further investigation.

And the science research goes on.

I really hope and believe that the scientists all over the world with the intensive study, will soon give answers, which will progress medicine knowledge for many diseases.

It’s an ill wind that blows something good.