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

doi:10.1016/j.isci.2022.103818

Attenuation of SARS-CoV-2 infection by losartan in human kidney organoids

iScience. 2022 Feb 18;25(2):103818. doi: 10.1016/j.isci.2022.103818. Epub 2022 Jan 28.

Authors

Waleed Rahmani^{1

2}, Hyunjae Chung², Sarthak Sinha³, Maxwell P Bui-Marinos^{2

4}, Rohit Arora³, Arzina Jaffer³, Jennifer A Corcoran^{2

4}, Jeff Biernaskie^{3

5

6}, Justin Chun^{1

2}

Affiliations

¹ Department of Medicine, Health Research Innovation Centre 4A12, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada.
² Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
³ 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.
⁴ Microbiology, Immunology and Infectious Diseases Department and Charbonneau Cancer Research Institute, University of Calgary, Calgary, AB, Canada.
⁵ Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
⁶ Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.

Abstract

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.

Keywords: Cell biology; Nephrology; Virology.