SuPAR mediates viral response proteinuria by rapidly changing podocyte function

Changli Wei (), Prasun K. Datta, Florian Siegerist, Jing Li, Sudhini Yashwanth, Kwi Hye Koh, Nicholas W. Kriho, Anis Ismail, Shengyuan Luo, Tracy Fischer, Kyle T. Amber, David Cimbaluk, Alan Landay, Nicole Endlich, Jay Rappaport, Salim S. Hayek () and Jochen Reiser ()
Additional contact information
Changli Wei: Rush University Medical Center
Prasun K. Datta: Tulane National Primate Research Center
Florian Siegerist: University Medicine Greifswald
Jing Li: Rush University Medical Center
Sudhini Yashwanth: Rush University Medical Center
Kwi Hye Koh: Morphic Therapeutic
Nicholas W. Kriho: Rush University Medical Center
Anis Ismail: University of Michigan
Shengyuan Luo: Rush University Medical Center
Tracy Fischer: Tulane National Primate Research Center
Kyle T. Amber: Rush University Medical Center
David Cimbaluk: Rush University Medical Center
Alan Landay: Rush University Medical Center
Nicole Endlich: University Medicine Greifswald
Jay Rappaport: Tulane National Primate Research Center
Salim S. Hayek: University of Michigan
Jochen Reiser: Rush University Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Elevation 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.

Date: 2023
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DOI: 10.1038/s41467-023-40165-5

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