Attenuation of SARS-CoV-2 infection by losartan in human kidney organoids
Waleed Rahmani,
Hyunjae Chung,
Sarthak Sinha,
Maxwell P. Bui-Marinos,
Rohit Arora,
Arzina Jaffer,
Jennifer A. Corcoran,
Jeff Biernaskie,
Justin Chun
Affiliations
Waleed Rahmani
Department of Medicine, Health Research Innovation Centre 4A12, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Hyunjae Chung
Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Sarthak Sinha
Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Heritage Medical Research Building, Room 402, 3300 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
Maxwell P. Bui-Marinos
Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Microbiology, Immunology and Infectious Diseases Department and Charbonneau Cancer Research Institute, University of Calgary, Calgary, AB, Canada
Rohit Arora
Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Heritage Medical Research Building, Room 402, 3300 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
Arzina Jaffer
Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Heritage Medical Research Building, Room 402, 3300 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
Jennifer A. Corcoran
Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Microbiology, Immunology and Infectious Diseases Department and Charbonneau Cancer Research Institute, University of Calgary, Calgary, AB, Canada
Jeff Biernaskie
Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Heritage Medical Research Building, Room 402, 3300 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Corresponding author
Justin Chun
Department of Medicine, Health Research Innovation Centre 4A12, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Corresponding author
Summary: COVID-19-associated acute kidney injury (COVID-AKI) is a common complication of SARS-CoV-2 infection in hospitalized patients. The susceptibility of human kidneys to direct SARS-CoV-2 infection and modulation of the renin-angiotensin II signaling (RAS) pathway by viral infection remain poorly characterized. Using induced pluripotent stem cell-derived kidney organoids, SARS-CoV-1, SARS-CoV-2, and MERS-CoV tropism, defined by the paired expression of a host receptor (ACE2, NRP1 or DPP4) and protease (TMPRSS2, TMPRSS4, FURIN, CTSB or CTSL), was identified primarily among proximal tubule cells. Losartan, an angiotensin II receptor blocker being tested in patients with COVID-19, inhibited angiotensin II-mediated internalization of ACE2, upregulated interferon-stimulated genes (IFITM1 and BST2) known to restrict viral entry, and attenuated the infection of proximal tubule cells by SARS-CoV-2. Our work highlights the susceptibility of proximal tubule cells to SARS-CoV-2 and reveals a putative protective role for RAS inhibitors during SARS-CoV-2 infection.
