Molecular processes in kidney cells may 'prime' diabetics for COVID-19 infection

October 23, 2020

People with diabetes -- especially the 20 to 40 percent with diabetic kidney disease -- are among the most at risk for serious complications and death from COVID-19. A new study of gene expression utilizing machine learning peered inside the kidney cells of COVID-19 patients and diabetic kidney disease patients and made a surprising discovery: Similar molecular processes were activated in both sets of patients, revealing potential avenues of viral vulnerability. The researchers Kidney International.

The results suggest that diabetes may predispose patients to infection with the novel coronavirus or to more severe COVID-19 by spurring biological processes used by the virus to infect and replicate. The same study found that medications commonly used to treat hypertension and diabetic kidney disease probably don't increase coronavirus infection risk, despite initial concerns about drug interactions with viral entry pathways.

"Our hypothesis is that diabetes primes these kidney cells in some way that makes them especially vulnerable to COVID," says study co-author Aaron Wong, a data scientist and project leader at the

The research was led by Olga Troyanskaya, deputy director of genomics at the CCB and a professor at Princeton University, and Matthias Kretzler, a nephrologist and a professor at the University of Michigan's academic medical center, Michigan Medicine. Wong is co-lead author of the study along with the CCB's Rachel Sealfon, Princeton's Chandra Theesfeld, and Michigan Medicine's Rajasree Menon, Edgar Otto and Viji Nair.

The coronavirus responsible for COVID-19, dubbed SARS-CoV-2, is best known for targeting cells in the respiratory system. However, the virus can also invade cells in organs such as the heart and kidneys. The virus infiltrates cells by latching on to a protein called angiotensin-converting enzyme 2, or ACE2. This viral piggybacking prompted the hypothesis that cells that produce lots of ACE2 are more vulnerable to infection. The researchers set out to find which kidney cells had elevated ACE2 levels and what made those cells extra vulnerable in diabetic kidney disease patients.

The researchers started by measuring ACE2 levels and gene expression in cells taken from biopsies from healthy kidney donors and patients with diabetic kidney disease. Kidney biopsies weren't an option for COVID-19 patients, so the researchers looked instead at kidney cells in urine samples from COVID-19 patients with kidney damage. These provided a unique look inside the organ without invasive procedures. Analyzing the samples, the researchers found ACE2 expression primarily in proximal tubule epithelial cells. These cells play a major role in the reabsorption of substances such as water, salt, glucose and amino acids by the kidneys.

Only around one-fifth of the proximal tubule epithelial cells had detectable ACE2 and were therefore vulnerable to infection. So what made those cells so vulnerable to COVID-19 in diabetic kidney disease patients? To find out, the researchers looked at which biological processes ramp up in ACE2-expressing cells. To identify these pathways in the vast complexity of cellular circuitry, researchers used the system developed by Troyanskaya's group at the CCB. HumanBase uses machine learning to identify biological connections between genes and pinpoint functionally related groups of genes (called modules) in the context of specific tissues, cell types and diseases. "HumanBase is what made this analysis possible," Troyanskaya says.

HumanBase identified several modules linked to ACE2 production in COVID-19 patients. Those modules were associated with processes related to a cell's reaction to viral invasion, the activation of immune responses, and viral replication. Surprisingly, those same modules were also present in patients with diabetic kidney disease. "The cells in the diabetic kidney patients looked a lot like the cells in the COVID-19 patients," says Sealfon, "with many genes upregulated that respond to or are engaged by viruses."

The consequences are twofold: Diabetic kidney disease could make cells more vulnerable to the coronavirus, and diabetic kidney disease and COVID-19 may compound each other's effects, potentially triggering a severe immune response that causes kidney damage.

The researchers also found that ACE2 levels were unaffected by drugs known as renin-angiotensin-aldosterone system inhibitors, which are commonly used to treat hypertension and diabetic kidney disease. These drugs modulate ACE or inhibit the pathway used by the protein. "At the beginning of the pandemic, there was a back-and-forth about whether patients should stop taking these ACE pathway modulators because they might increase the risk of infection," Theesfeld says. "Now a few studies, including ours, show that they should keep taking their medicines."

The results come with a major caveat, though. The study looked at the gene expression in kidney cells from patients with diabetes or COVID-19, but not both. More work is needed to confirm how the two illnesses behave in tandem. The researchers say that the next step is to look at kidney tissues affected by both diabetic kidney disease and COVID-19. Such a study could help identify whether specific therapies could reduce COVID-19 susceptibility and progression in diabetic kidney disease patients.

The Flatiron Institute is the research division of the Simons Foundation. The institute's mission is to advance scientific research through computational methods, including data analysis, modeling and simulation. The institute's Center for Computational Biology develops new and innovative methods of examining data in the biological sciences whose scale and complexity have historically resisted analysis. The center's mission is to develop modeling tools and theory for understanding biological processes and to create computational frameworks that will enable the analysis of the large, complex data sets being generated by new experimental technologies.

Simons Foundation

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to