SuPAR mediates viral response proteinuria by rapidly changing podocyte function

• Published in: Nature communications Vol. 14; no. 1; pp. 4414 - 12
• Main Authors: Wei, Changli, Datta, Prasun K., Siegerist, Florian, Li, Jing, Yashwanth, Sudhini, Koh, Kwi Hye, Kriho, Nicholas W., Ismail, Anis, Luo, Shengyuan, Fischer, Tracy, Amber, Kyle T., Cimbaluk, David, Landay, Alan, Endlich, Nicole, Rappaport, Jay, Hayek, Salim S., Reiser, Jochen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.07.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 38; 631/45/127; 64; 692/4022; 692/699/255/2514; Animals; Antibodies; Chlorocebus aethiops; Coronaviruses; COVID-19; COVID-19 Vaccines; Humanities and Social Sciences; Humans; Inoculation; Integrins; Kidney diseases; Mice; multidisciplinary; Podocytes; Proteins; Proteinuria; Receptors; Receptors, Urokinase Plasminogen Activator - genetics; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Thrombolytic drugs; U-Plasminogen activator; Urokinase; Vaccination; Viral diseases; Viral infections
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40165-5

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. Proteinuric kidney diseases are on the rise and have limited treatment options. Here, the authors show soluble urokinase receptor (suPAR) orchestrates viral response proteinuria (VRP) which occurs in response to certain viral infections and podocyte integrin engagement.