SuPAR mediates viral response proteinuria by rapidly changing podocyte function

Author:

Wei ChangliORCID,Datta Prasun K.,Siegerist FlorianORCID,Li Jing,Yashwanth Sudhini,Koh Kwi HyeORCID,Kriho Nicholas W.,Ismail Anis,Luo Shengyuan,Fischer TracyORCID,Amber Kyle T.,Cimbaluk David,Landay Alan,Endlich Nicole,Rappaport Jay,Vasbinder Alexi,Anderson Elizabeth,Catalan Tonimarie,Pizzo Ian,Bitterman Brayden,Erne Grace,Machado-Diaz Kristen,Presswalla Feriel,Nelapudi Namratha,Amadi Kingsley-Michael,Bardwell Alina,Blakely Pennelope,Huang Yiyuan,Banerjee Mousumi,Pop-Busui Rodica,Hayek Salim S.ORCID,Reiser JochenORCID,

Abstract

AbstractElevation in soluble urokinase receptor (suPAR) and proteinuria are common signs in patients with moderate to severe coronavirus disease 2019 (COVID-19). Here we characterize a new type of proteinuria originating as part of a viral response. Inoculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes increased suPAR levels and glomerulopathy in African green monkeys. Using an engineered mouse model with high suPAR expression, inhaled variants of SARS-CoV-2 spike S1 protein elicite proteinuria that could be blocked by either suPAR antibody or SARS-CoV-2 vaccination. In a cohort of 1991 COVID-19 patients, suPAR levels exhibit a stepwise association with proteinuria in non-Omicron, but not in Omicron infections, supporting our findings of biophysical and functional differences between variants of SARS-CoV-2 spike S1 protein and their binding to podocyte integrins. These insights are not limited to SARS-CoV-2 and define viral response proteinuria (VRP) as an innate immune mechanism and co-activation of podocyte integrins.

Funder

U.S. Department of Health & Human Services | National Institutes of Health

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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