Abstract
Old-world orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), characterized by acute kidney injury (AKI) with transient proteinuria. It seems plausible that proteinuria during acute HFRS is mediated by the disruption of the glomerular filtration barrier (GFB) due to vascular leakage, a hallmark of orthohantavirus-caused diseases. However, direct infection of endothelial cells by orthohantaviruses does not result in increased endothelial permeability, and alternative explanations for vascular leakage and diminished GFB function are necessary. Vascular integrity is partly dependent on an intact endothelial glycocalyx, which is susceptible to cleavage by heparanase (HPSE). To understand the role of glycocalyx degradation in HFRS-associated proteinuria, we investigated the levels of HPSE in urine and plasma during acute, convalescent and recovery stages of HFRS caused by Puumala orthohantavirus. HPSE levels in urine during acute HFRS were significantly increased and strongly associated with the severity of AKI and other markers of disease severity. Furthermore, increased expression of HPSE was detected in vitro in orthohantavirus-infected podocytes, which line the outer surfaces of glomerular capillaries. Taken together, these findings suggest the local activation of HPSE in the kidneys of orthohantavirus-infected patients with the potential to disrupt the endothelial glycocalyx, leading to increased protein leakage through the GFB, resulting in high amounts of proteinuria.
| Original language | English |
|---|---|
| Article number | 450 |
| Journal | Viruses |
| Volume | 14 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 22 Feb 2022 |
Bibliographical note
Funding Information:This research was funded by the Academy of Finland (grant number 321809, to T.S.), Sigrid Jusélius Foundation (grant number MS568, to A.V. and J.M.), Magnus Ehrnrooth Foundation (to A.V.), Finnish Kidney Foundation/Munuaissäätiö (to L.E.C.), Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital (grant numbers 9X033 and 9V040, to J.M. and S.M.) and Tampere Tuberculosis Foundation (grant number MS759, to J.M.).We thank Sanna Mäki and Päivi Yli–Nikkilä for the expert technical assistance. Open Access Funding provided by University of Helsinki.
Funding Information:
Funding: This research was funded by the Academy of Finland (grant number 321809, to T.S.), Sigrid Jusélius Foundation (grant number MS568, to A.V. and J.M.), Magnus Ehrnrooth Foundation (to A.V.), Finnish Kidney Foundation/Munuaissäätiö (to L.E.C.), Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital (grant numbers 9X033 and 9V040, to J.M. and S.M.) and Tampere Tuberculosis Foundation (grant number MS759, to J.M.).
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.