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.
CITATION Cell Metab. 2022 Jun 7;34(6):857-873.e9. doi: 10.1016/j.cmet.2022.04.009. Epub 2022 May 12