Although the lungs are a common target for COVID-19’s cytokine storm, so are the kidneys, making the 1 in 4 U.S. adults with diabetes resulting in diabetic kidney disease at increased risk for virus mortality, according to research from the University of Michigan (UMICH).
Recently published in Kidney International, a national research team made up of kidney clinicians, bioinformaticians, a molecular biologist, pathologist and virologist found that a protein on the surface of some kidney cells, called angiotensin-converting enzyme 2 (ACE2), is the primary COVID-19 entry receptor and aids in the activation of its uncontrolled immune response. It also is responsible for the virus’ duplication, leaving patients sicker, longer.
Since higher levels of ACE2 expression on cells correlates with higher risk of serious COVID-19 illness, Matthias Kretzler, MD, a study author and nephrologist at Michigan Medicine, sought out to learn more about which kidney cells create elevated levels of this protein and why, as well as if the molecular process of the vulnerable cells is similar to those in patients with COVID-19.
Using machine learning technology developed by study author Olga Troyanskaya, PhD, from Princeton University, the researchers were able to identify and categorize groups of genes that produced higher ACE2 expression levels in three different subject groups: healthy, living kidney donors (18 participants), those with diabetic kidney disease (44 participants) and those hospitalized with COVID-19 (13 participants). After analyzing more than 110,000 different cells in the three groups, Kretzler and the team identified networks of molecules that result in higher levels of ACE2.
The groups shared a few molecular similarities, but one would become the focus of the researchers: ACE2 was predominantly expressed in cells that also expressed markers of specialized transport epithelial cells in the proximal tubules. Using kidney biopsies from the healthy kidneys and those with diabetic kidney disease, and kidney cells retrieved from the urine samples of COVID-19 patients, the machine learning technology allowed the research team to pinpoint in what kidney cells ACE2 is found and what characteristics these cells have.
Discovering the importance of the proximal tubules’ epithelial cells in its relation to the severity of COVID-19 illness opens a door for novel therapeutics to address COVID-19 and its related kidney injury.
