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Lab-generated mini-kidneys help understand why diabetes patients are more at risk from COVID

MADRID, 12 May. (EUROPA PRESS) –

A group of international researchers, including Spanish research centers, has shown that diabetic mini-kidneys have a greater susceptibility to SARS-CoV-2 infection, as well as genetic evidence of the essential role of the ACE2 receptor in COVID-19. .

In addition, they have identified that the metabolic programming caused by diabetes is critical and increases susceptibility to SARS-CoV-2 infection in the kidney. These results may lead to the identification of new interventions in the pathogenesis of COVID-19 targeting energy metabolism.

In this international collaboration, researchers led by Nuria Montserrat, ICREA research professor at the Institute of Bioengineering of Catalonia (IBEC) and principal investigator of the “Pluripotency for organ regeneration” group, have generated human mini-kidneys that simulate a person’s kidney with diabetes in the early stages of the disease. These diabetic mini-kidneys open the door to study, among others, the relationship between diabetes and COVID-19.

For two years, thousands of scientists and doctors around the world have been working to understand how COVID-19 develops and how it is related to other types of diseases. Various studies indicate that people with diabetes are more likely to develop severe COVID-19, and that more than 20% of patients hospitalized for COVID-19 suffer from acute kidney injury. However, to date it was unknown what was the factor that caused this to happen.

Now, the international team led by Nuria Montserrat in collaboration, among others, with researchers from the University of Florida, the Institute of Life Sciences of the University of British Columbia in Canada, the Karolinska Institute and the Karolinska University Hospital in Sweden have used bioengineering to develop mini-kidneys that simulate the kidney of a person in the early stages of diabetes.

In this international collaboration, researchers have provided, for the first time, the use of renal organoids to understand the early stages of diabetes in this organ. To demonstrate that the ACE2 receptor plays an essential role in SARS-CoV-2 infection in the kidney, the team has also used genetic engineering to generate defective organoids for other receptors described to date as portals of entry for the virus.

Using kidney cells from patients, this study, published in the journal Cell Metabolism, also reveals the role of energy metabolism in SARS-CoV-2 infection, opening the door to the identification of new therapeutic interventions to treat COVID-19 .

DEVELOPMENT OF THE MINI-KIDNEYS

Mini-kidneys have been grown in the laboratory from pluripotent human stem cells. To replicate the diabetic environment, the researchers have subjected the mini-kidneys to culture conditions that result in the generation of mini-kidneys with the same cellular characteristics and metabolic abnormalities as those found in the kidneys of a person with early-stage diabetes.

Using different molecular biology techniques, such as gene editing, researchers have observed that, in diabetic mini-kidneys, it is the abundance of the ACE2 receptor that determines susceptibility to viral infection, establishing a causal relationship between diabetes and the presence of one of the receptors described so far as determinants in SARS-CoV-2 infection.

“Our diabetic renal organoid model has allowed us to observe that diabetic mini-kidneys, with a greater number of ACE2 receptors, are more susceptible to viral infection”, says Elena Garreta, Institute of Bioengineering of Catalonia and first co-author of the study.

To see if the results obtained with the mini-kidneys are also observed in the native organ, the researchers analyzed kidney cells from patients with diabetes and individuals without diabetes. The data show that renal cells from diabetic patients, as in mini-kidneys, have more ACE2 receptors and suffer a higher rate of SARS-CoV-2 infection. To delve into the mechanisms that may explain such observations, the researchers used a compound that modulates the metabolic state of cells and found that the treatment reduced viral infection.

“This finding sheds light on a potential mechanism behind the most severe cases of diabetic patients. This technology will improve our ability to investigate how the virus interacts with different organs in the human body,” said Ali Mirazimi, Associate Professor at Karolinska Institutet and one of the corresponding authors of the study.

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