ACE inhibition in kidney could influence pathogenesis of SARS-CoV-2

By Sally Robertson, B.Sc.Jun 24 2020

The dynamics of angiotensin-converting enzyme 2 (ACE2) expression in the kidney could have implications for the infectivity and pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), say researchers.

Given that ACE2 is the receptor for SARS-CoV-2, concerns have arisen over whether altered ACE2 expression among patients taking ACE inhibitors or angiotensin receptor blockers (ARBs) influences the disease process.

Now, a study led by researchers at the Broad Institute of MIT, Brigham And Women's Hospital, Helmholtz Zentrum München and Harvard has identified a significant increase in ACE2 expression with ACE inhibitor/ARB use in the proximal convoluted tubule, thick ascending limb, and endothelial cells of the kidney.

However, a further mechanistic investigation among larger cohorts is needed, says the team, since the association was likely confounded by underlying disease in this small cohort.

A pre-print version of the paper can be accessed on the server bioRxiv*, while the article undergoes peer review.

SARS-CoV-2 viruses binding to ACE-2 receptors on a human cell, the initial stage of COVID-19 infection, conceptual 3D illustration Credit: Kateryna Kon / Shutterstock

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

COVID-19 affects multiple organs, including the kidney

SARS-CoV-2 – the causative agent of coronavirus disease 2019 (COVID-19) – initiates infection by binding to the ACE2 receptor on human host cells.

Aside from respiratory tissues such as the lung and nasal epithelium, studies have shown that COVID-19 affects a range of organs, including the kidney.

However, not enough is known about cell-specific ACE2 expression in the kidney for researchers to account for factors such as age and sex, which are known to influence susceptibility to SARS-CoV-2 and disease severity.

The Renin-Angiotensin-Aldosterone System

ACE2 is a vital component of the Renin-Angiotensin-Aldosterone System (RAAS), which regulates blood pressure and inflammation, mainly through effects exerted on the kidney.

ACE2 converts angiotensin I and angiotensin II into vasodilatory peptides, which balances the effects of the RAAS when ACE converts angiotensin I into the vasoconstrictor angiotensin II.

Treatment approaches to high blood pressure, cardiovascular conditions, and chronic kidney disease often involve targeting the RAAS with ACE inhibitors or ARBs to stop ACE converting angiotensin I into angiotensin II or to stop angiotensin II binding to its receptor.

The effect of RAAS blockade on ACE2 expression is unclear

To date, the association between the use of ACE inhibitors/ARBs and ACE2 expression and activity is not well understood, but widespread debate surrounds the topic since ACE2 is the receptor for SARS-CoV-2.

Furthermore, the ACE2 gene is located on the X chromosome, and the SARS-CoV-2 infection has been associated with more severe disease in men.

Now, Anna Greka and colleagues have used individual human kidney cell transcriptomic data to assess the effects of age and sex on ACE2 expression in the kidney and investigate whether the use of ACE inhibitors and ARBs is linked to altered expression.

A significant association between age, sex and ACE2 expression in the kidney

Covariate analysis of 176,421 cells across 49 kidney donors (29 males, 20 females; median age 57) identified a significant association between age, sex, and ACE2 expression in tubular epithelial cells of the thin loop of Henle (tLoH).

At younger ages, ACE2 expression in tLoH cells was significantly increased among males, compared with females. However, with increasing age, an upwards trend in ACE2 expression was observed among females, while a downward trend was observed among males.

“Overall, the sex effect was statistically significant at younger ages, where males had higher expression relative to females. With older ages, the gap narrows, eventually reversing direction and is no longer significant,” writes the team.

Testing for an association between ACE inhibitors/ARBs and ACE2 expression

To test for an association between the use of ACE inhibitors/ARBs and ACE2 expression, the researchers used nine kidney biopsies with various features of renal disease and two cortical nephrectomy samples from patients with glomerulosclerosis.

Analysis using fixed and random effects models accounting for age and sex found that the use of the drugs was associated with a significant increase in ACE2 expression in the proximal convoluted tubule (PCT), thick ascending limb (TAL) and endothelial cells (EC) of the kidney.

However, when the team’s effect models adjusted for the disease category, Lupus nephritis was significantly associated with ACE2 expression in PCT, TAL, and EC.

“The use of ACE inhibitors/ARBs was likely confounded with underlying Lupus nephritis in relation to ACE2 levels in the proximal tubular, thick ascending limb and endothelial cells in the kidney after adjustment for age and sex,” write Greka and colleagues.

“Further mechanistic investigation” is needed

The researchers say the further mechanistic investigation and studies involving larger patient cohorts are needed to assess whether ACE2 expression is beneficial or harmful in the context of disease or RAAS blockade.

“Whether such transcriptional changes also play a role in SARS-CoV-2 tropism for the kidney remains an open question that we may only be able to confidently answer once large clinical cohorts are analyzed at the end of the current pandemic,” concludes the team.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.