Laboratory-generated mini-kidneys help understand the link between diabetes and COVID-19 disease

• In an international collaboration, researchers led by Nuria Montserrat, ICREA Research Professor at IBEC, have generated human mini-kidneys that simulate the kidney of a person with diabetes in the early stages of the disease. These diabetic mini-kidneys open the door to studying, among others, the relationship between diabetes and COVID-19. 

• The researchers demonstrated that diabetic mini-kidneys have a higher susceptibility to SARS-CoV-2 infection, as well as genetic evidence for the essential role of the ACE2 receptor in COVID-19. These observations have been confirmed in kidney cells from diabetic patients. 

• 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.

Barcelona, May 9^th, 2022.

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

Now, an international team 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, in collaboration with, among others, researchers from the University of Florida, the Life Sciences Institute of the University of British Columbia in Canada, Karolinska Institutet and 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 the researchers have provided, for the first time, the use of kidney organoids to understand the early stages of diabetes in this organ. In order 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 gateways for the virus. Using patient kidney cells, this study 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. This groundbreaking study has just been published in the prestigious journal Cell Metabolism.

Diabetic mini-kidneys have more portals of entry for SARS-CoV-2

Mini-kidneys have been developed in the laboratory from pluripotent human stem cells. To reproduce 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 alterations as those found in the kidneys of a person with early-stage diabetes.

Using different molecular biology techniques, such as gene editing, the 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 determinant 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, have a greater susceptibility to viral infection.”

Elena Garreta, Institute for Bioengineering of Catalonia and first co-author of the study

“It is absolutely imperative to understand the molecular mechanisms that underlie more severe COVID-19 in patients with diabetes and other metabolic comorbidities. The development of a diabetic kidney organoid is a great step towards experimentally dissecting how metabolic changes can impact SARS-CoV-2 infections. The data again demonstrate that ACE2 is the essential receptor for SARS-CoV-2 even under conditions of comorbidity.”

Josef Penninger, Institute of Molecular Biotechnology

Furthermore, using state-of-the-art techniques such as RNA sequencing, the researchers identified that diabetic mini-kidneys have a metabolic signature that could explain why diabetic mini-kidneys become more infected.

Diabetes increases susceptibility to SARS-CoV-2 infection in patient cells.

To verify whether 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 kidney cells from diabetic patients, in the same way as what happens 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 a light on a potential mechanism behind more severe cases of diabetic patients. This technology will improve our capability to investigate how the virus interacts with different organs in the human body.”

Ali Mirazimi, adjunct professor at Karolinska Institutet and one of the study’s corresponding authors.

"We have shown that the SARS-CoV-2 virus is capable of directly infecting proximal tubule cells isolated from the human kidney and that diabetes makes these cells more prone to infection."

Megan Stanifer, first co-author of the study (University of Florida)

This research was supported in part by the Institute of Health Carlos III and the Foundation Banco Bilbao Vizcaya through emergency funding focused on accelerating the development, testing, and implementation of measures to deal with the COVID-19 outbreak.

Reference article:

Elena Garreta, Patricia Prado, Megan Stanifer, Vanessa Monteil, Andrés Marco, Asier Ullate-Agote, Daniel Moya-Rull, Amaia Vilas-Zornoza, Carolina Tarantino, Juan Pablo Romero, Gustav Jonsson, Roger Oria, Alexandra Leopoldi, Astrid Hagelkruys, Maria Gallo, Federico González, Pere Domingo-Pedrol, Aleix Gavaldà, Carmen Hurtado del Pozo, Omar Hasan Ali, Pedro Ventura-Aguiar, Josep María Campistol, Felipe Prosper, Ali Mirazimi, Steeve Boulant, Josef M. Penninger, Nuria Montserrat. A diabetic milieu increases ACE2 expression and cellular susceptibility to SARS-CoV-2 infections in human kidney organoids and patient cells. Cell Metabolism.

About the Institute for Bioengineering of Catalonia

The Institute for Bioengineering of Catalonia (IBEC) is a leading-edge multidisciplinary research centre based in Barcelona that conducts research at the frontiers of basic and life sciences linked with engineering to generate new knowledge and applications that helps to enhance health and quality of life. IBEC create wealth by putting together biophysics, cell engineering, nanomedicine, biomaterials, tissue engineering and the applications of information technology to health. IBEC is a non-profit-making foundation set up in 2005 by the Departments of Health and Innovation, Universities and Enterprise of the Government of Catalonia, the University of Barcelona and the Technical University of Catalonia. http://www.ibecbarcelona.eu/

About LSI

The Life Sciences Institute (LSI) at the University of British Columbia conducts basic research aimed at improving human and planetary health. Home to 17 prestigious Canada Research Chairs, the LSI hosts multidisciplinary teams working to develop a comprehensive understanding of living organisms and systems. Members of our nine research groups conduct world-class research in diabetes, cardiovascular disease, immune response, infectious disease, cancer biology, developmental disorders, bacterial regulation, neuroscience, structural biology, environmental microbiology and molecular epigenetics.

Launched in 2005 in association with the UBC Faculties of Science and Medicine, LSI houses the vibrant research labs of 87 investigators drawn from 15 departments across five faculties. We collaborate in the 270,000 s.f. Life Sciences Centre, where seven state-of-the-art core facilities – ranging from flow cytometry to cryo-electron microscopy and bioformatics – support discoveries that hold promise of direct health benefits for Canadians and Canada.

About University of British Columbia (UBC)

The University of British Columbia is a global centre for research and teaching, consistently ranked among the top 20 public universities in the world. Since 1915, UBC’s entrepreneurial spirit has embraced innovation and challenged the status quo. UBC encourages its students, staff and faculty to challenge convention, lead discovery and explore new ways of learning. At UBC, bold thinking is given a place to develop into ideas that can change the world. 

About Karolinska Institutet

Karolinska Institutet is one of the world’s leading medical universities. Our vision is to advance knowledge about life and strive towards better health for all. Karolinska Institutet accounts for the single largest share of all academic medical research conducted in Sweden and offers the country’s broadest range of education in medicine and health sciences. The Nobel Assembly at Karolinska Institutet selects the Nobel laureates in Physiology or Medicine.