A diabetic milieu increases ACE2 expression and cellular susceptibility to SARS-CoV-2 infections in human kidney organoids and patient cells
Elena Garreta, Patricia Prado, Megan L. Stanifer, Vanessa Monteil, Andrés Marco, Asier Ullate‐Agote, Daniel Moya‐Rull, Amaia Vilas‐Zornoza, Carolina Tarantino, Juan P. Romero, Gustav Jonsson, Roger Oria, Alexandra Leopoldi, Astrid Hagelkrüys, Maria Gallo, Federico Gonzãlez, Pere Domingo‐Pedrol, Aleix Gavaldà‐Navarro, Carmen Hurtado del Pozo, Omar Hasan Ali, Pedro Ventura‐Aguiar, Josep M. Campistol, Felipe Prósper, Alì Mirazimi, Steeve Boulant, Josef Penninger, Núria Montserrat
Abstract
It is not well understood why diabetic individuals are more prone to develop severe COVID-19. To this, we here established a human kidney organoid model promoting early hallmarks of diabetic kidney disease development. Upon SARS-CoV-2 infection, diabetic-like kidney organoids exhibited higher viral loads compared with their control counterparts. Genetic deletion of the angiotensin-converting enzyme 2 (ACE2) in kidney organoids under control or diabetic-like conditions prevented viral detection. Moreover, cells isolated from kidney biopsies from diabetic patients exhibited altered mitochondrial respiration and enhanced glycolysis, resulting in higher SARS-CoV-2 infections compared with non-diabetic cells. Conversely, the exposure of patient cells to dichloroacetate (DCA), an inhibitor of aerobic glycolysis, resulted in reduced SARS-CoV-2 infections. Our results provide insights into the identification of diabetic-induced metabolic programming in the kidney as a critical event increasing SARS-CoV-2 infection susceptibility, opening the door to the identification of new interventions in COVID-19 pathogenesis targeting energy metabolism.