Soluble urokinase receptor is a kidney-specific vasoconstrictor

Background: Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune system-derived risk factor for acute and chronic kidney diseases. While suPAR effects on kidney epithelial cells have been reported, its impact on renal vasculature remains unknown. Methods: We investigated how suPAR affects renal blood flow and glomerular dynamics using a translational approach integrating clinical observations from a propensity-score-matched cardiac surgery cohort, ex vivo porcine kidney perfusion, and intravital multiphoton imaging in mice. Findings: In the matched clinical cohort, we found a significant inverse correlation between suPAR levels and baseline kidney function, with mean eGFR values 14.5 mL/min/1.73 m² lower in the high suPAR group (≥4 ng/mL) compared to the low suPAR group (<4 ng/mL). Patients with high suPAR levels had significantly higher AKI occurrence (56% vs 33%; relative risk 1.71, 95% CI 1.37–2.12). In experimental models, suPAR caused immediate reduction in renal blood flow and triggered robust calcium responses in renal contractile cells, particularly the extraglomerular mesangium. These effects were absent in brain vasculature and were antagonised by an anti-uPAR antibody. Interpretation: Unlike many immune mediators, suPAR causes predominantly kidney-specific vasoconstriction, establishing a new class of innate-immune vasoconstrictors with direct implications for causing acute kidney injury in high-risk patients. Funding: Supported by the National Institutes of Health, University of Southern Denmark, Region of Southern Denmark PhD Fund, OUH-RH Joint Research Fund, Danish Kidney Association's Research Fund, Odense University Hospital Research Fund, Goldsmith A. L. Rasmussen Memorial Fund, Dept. of Anaesthesiology-Intensive Care, OUH Research Fund and the MeCiSu Frontline Centre.