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.
Keywords: ACE2; COVID-19; SARS-CoV-2; angiotensin-converting enzyme 2; diabetes 2; human kidney organoids.
【저자키워드】 COVID-19, SARS-CoV-2, ACE2, angiotensin-converting enzyme 2, diabetes 2, human kidney organoids., 【초록키워드】 severe COVID-19, SARS-COV-2 infection, susceptibility, Intervention, diabetes, angiotensin-converting enzyme 2, metabolism, kidney, COVID-19 pathogenesis, Viral load, cells, energy metabolism, Patient, Kidney disease, Viral detection, organoids, inhibitor, Critical, SARS-CoV-2 infections, Angiotensin-converting enzyme, Glycolysis, diabetic patients, angiotensin, biopsy, mitochondrial, aerobic glycolysis, diabetic kidney, Diabetic, enzyme, individual, door, hallmark, human kidney, aerobic, programming, Cell, kidney organoids, dichloroacetate, diabetic patient, resulting, develop, reduced, exhibited, condition, prevented, diabete, kidney organoid, 【제목키워드】 susceptibility, Patient, ACE2 expression, cellular, Organoid, human kidney, Cell, increase,