A diabetic milieu increases ACE2 expression and cellular susceptibility to SARS-CoV-2 infections in human kidney organoids and patient cells

Elena Garreta 1, Patricia Prado 1, Megan L Stanifer 2, Vanessa Monteil 3, Andrés Marco 1, Asier Ullate-Agote 4, Daniel Moya-Rull 1, Amaia Vilas-Zornoza 4, Carolina Tarantino 1, Juan Pablo Romero 5, Gustav Jonsson 6, Roger Oria 7, Alexandra Leopoldi 6, Astrid Hagelkruys 6, Maria Gallo 1, Federico González 1, Pere Domingo-Pedrol 8, Aleix Gavaldà 9, Carmen Hurtado Del Pozo 1, Omar Hasan Ali 10, Pedro Ventura-Aguiar 11, Josep María Campistol 11, Felipe Prosper 4, Ali Mirazimi 12, Steeve Boulant 13, Josef M Penninger 14, Nuria Montserrat 15

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.