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

Publication

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

Journal Paper/Review - May 12, 2022

Garreta Elena, Prado Patricia, Stanifer Megan L, Monteil Vanessa, Marco Andrés, Ullate-Agote Asier, Moya-Rull Daniel, Vilas-Zornoza Amaia, Tarantino Carolina, Romero Juan Pablo, Jonsson Gustav, Oria Roger, Leopoldi Alexandra, Hagelkruys Astrid, Gallo Cantafio Maria Eugenia, González Federico, Domingo-Pedrol Pere, Gavaldà Aleix, Del Pozo Carmen Hurtado, Hasan Ali Omar, Ventura-Aguiar Pedro, Campistol Josep María, Prosper Felipe, Mirazimi Ali, Boulant Steeve, Penninger Josef M, Montserrat Nuria

Citation

Garreta E, Prado P, Stanifer M, Monteil V, Marco A, Ullate-Agote A, Moya-Rull D, Vilas-Zornoza A, Tarantino C, Romero J, Jonsson G, Oria R, Leopoldi A, Hagelkruys A, Gallo Cantafio M, González F, Domingo-Pedrol P, Gavaldà A, Del Pozo C, Hasan Ali O, Ventura-Aguiar P, Campistol J, Prosper F, Mirazimi A, Boulant S, Penninger J, Montserrat N. A diabetic milieu increases ACE2 expression and cellular susceptibility to SARS-CoV-2 infections in human kidney organoids and patient cells. Cell Metab 2022; 34:857-873.e9.

Type

Journal Paper/Review (English)

Journal

Cell Metab 2022; 34

Publication Date

May 12, 2022

Issn Electronic

1932-7420

Pages

857-873.e9

Brief description/objective

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.