Endothelial cell–released CD93 contributes to podocyte injury in idiopathic nephrotic syndrome

Idiopathic nephrotic syndrome (INS) is a podocyte disease triggered by immune-derived factors. Endothelial activation occurs in this context, but whether the activated endothelium contributes to podocyte injury is unknown. We tested the hypothesis that CD93, a protein primarily expressed in the endothelium, is a contributory factor of podocyte injury. We studied 460 patients with INS and 150 with other podocytopathies. CD93 was analyzed in kidney tissue, urine, and serum samples. We tested the efficacy of CD93 blockade in vitro and in vivo and investigated the relationship between soluble CD93 and clinical outcomes in human INS. CD93 was highly expressed by glomerular endothelial cells (GEnCs) in human INS, and INS sera stimulated cultured human GEnCs to release CD93. Mechanistically, soluble CD93 mediated podocyte activation via β1 integrin/FAK signaling in cultured human podocytes. CD93 blockade mitigated the activation of cultured human podocytes and albumin permeability in human GEnC-podocyte cocultures as well as albuminuria, glomerulosclerosis, and podocyte loss in two models of nephrotic syndrome: podocyte-specific transforming growth factor-β1 signaling (<i>PodTgfbr1</i>) mice and adriamycin-treated mice. <i>Cd93</i> knockout mice showed less proteinuria and glomerulosclerosis, compared with controls, after adriamycin injection. In patients with INS, soluble CD93 was high in urine in ~90% and 50% of patients in relapse and remission, respectively. High urinary CD93 was associated with faster decline in kidney function and slower response to immunosuppression. Soluble and glomerular CD93 was also elevated in other podocytopathies. We conclude that soluble CD93 contributes to podocyte injury.

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Publication Details

Journal
Science Translational Medicine
Published
2026-01-14
DOI
https://doi.org/10.1126/scitranslmed.adw2206
Citations
1
Primary Topic
Renal Diseases and Glomerulopathies
Type
article
Field-Weighted Citation Impact
34.94
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article

Endothelial cell–released CD93 contributes to podocyte injury in idiopathic nephrotic syndrome

Bradford Siegele, Aleksandra Żurowska, Pavel Davizon‐Castillo, Stefano da Sacco et al.
1 citations
Science Translational Medicine
Renal Diseases and Glomerulopathies
34.94
article

Endothelial cell–released CD93 contributes to podocyte injury in idiopathic nephrotic syndrome

Bradford Siegele, Aleksandra Żurowska, Pavel Davizon‐Castillo, Stefano da Sacco, Elena Levtchenko, Phillip J. McCown, J. Craig Hartman, S Tsuji, Andrés-Hernando Ana, Mindy Banks, Juan David González-Rodríguez, Colin Bauer, Ahsen Yılmaz, Julie Dougherty, Guadalupe Rojas-Sánchez, M. Kretzler, Danielle E. Soranno, P. Bjornstad, Cristina Aparicio-López, Flor A. Ordóñez-Álvarez, S. Eddy, José Eugenio Cabrera-Sevilla, Ilse S Daehn, Brad Rovin, Xin Wang, Cristina Martínez, Claudia Carrera-Muñoz, M. A. Lanaspa, A. H. M. Bouts, Audrey Rose Fetsko, Federica Piani, Gabriel Cara-Fuentes, Imtiazul Islam, M. Scott Lucia, Christopher L. O’Connor, Kazunari Kaneko, William E. Smoyer, Laura Mariani, Laura Perin, Markus Bitzer, Serena Zhao, Xiaolan L. Zhang, Franz Schaefer, Jonathan Troost, Christine B. Sethna, Alfons Segarra, Anna Dimberg, Yuwen Zhu, Bryce A. Kerlin, Liping Yu, Richard J. Johnson
article en
1 citations

Abstract

Idiopathic nephrotic syndrome (INS) is a podocyte disease triggered by immune-derived factors. Endothelial activation occurs in this context, but whether the activated endothelium contributes to podocyte injury is unknown. We tested the hypothesis that CD93, a protein primarily expressed in the endothelium, is a contributory factor of podocyte injury. We studied 460 patients with INS and 150 with other podocytopathies. CD93 was analyzed in kidney tissue, urine, and serum samples. We tested the efficacy of CD93 blockade in vitro and in vivo and investigated the relationship between soluble CD93 and clinical outcomes in human INS. CD93 was highly expressed by glomerular endothelial cells (GEnCs) in human INS, and INS sera stimulated cultured human GEnCs to release CD93. Mechanistically, soluble CD93 mediated podocyte activation via β1 integrin/FAK signaling in cultured human podocytes. CD93 blockade mitigated the activation of cultured human podocytes and albumin permeability in human GEnC-podocyte cocultures as well as albuminuria, glomerulosclerosis, and podocyte loss in two models of nephrotic syndrome: podocyte-specific transforming growth factor-β1 signaling (<i>PodTgfbr1</i>) mice and adriamycin-treated mice. <i>Cd93</i> knockout mice showed less proteinuria and glomerulosclerosis, compared with controls, after adriamycin injection. In patients with INS, soluble CD93 was high in urine in ~90% and 50% of patients in relapse and remission, respectively. High urinary CD93 was associated with faster decline in kidney function and slower response to immunosuppression. Soluble and glomerular CD93 was also elevated in other podocytopathies. We conclude that soluble CD93 contributes to podocyte injury.

Science Translational MedicineVol. 18(832)
Kansai Medical University (JP), Nationwide Children's Hospital (US), Children's Mercy Hospital (US), Children's Hospital of Los Angeles (US), University of Washington (US), Heidelberg University (DE), University of Michigan (US), Bloodworks Northwest (US), Science for Life Laboratory (SE), Hospital Universitari Arnau de Vilanova (ES), University Hospital Heidelberg (DE), Children's Hospital Colorado (US), Vall d'Hebron Institut de Recerca (ES), Hospital Infantil Universitario Niño Jesús (ES), Cohen Children's Medical Center (US), Azienda USL di Bologna (IT), Rocky Mountain Hospital for Children (US), Hospital Universitario Central de Asturias (ES), Santa Lucía University General Hospital (ES), Amsterdam University Medical Centers (NL), University of Colorado Anschutz Medical Campus (US), The Ohio State University (US), Indiana University – Purdue University Indianapolis (US), Istanbul University (TR), Gdańsk Medical University (PL), University of Colorado Denver (US), Icahn School of Medicine at Mount Sinai (US)
Good health and well-being
Openalex Percentile: Top 2%
Renal Diseases and Glomerulopathies
34.94
DOIOpen Access PDFOpenAlex
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