Reduced nephrin tyrosine phosphorylation impairs podocyte force transmission and accelerates detachment in disease
Summary: Podocytes are specialized kidney cells that form the slit diaphragm (SD), an intercellular filtration barrier against plasma protein loss. The SD is subject to significant mechanical strain which can be amplified in disease, leading to podocyte detachment. One key SD protein that might inte...
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Elsevier
2025-06-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225009344 |
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| author | Casey R. Williamson Claire E. Martin J. Dinesh Kumar Peihua Lu Laura A. New Alice Y. Wang Nils M. Kronenberg Malte C. Gather Paul A. Reynolds Nina Jones |
| author_facet | Casey R. Williamson Claire E. Martin J. Dinesh Kumar Peihua Lu Laura A. New Alice Y. Wang Nils M. Kronenberg Malte C. Gather Paul A. Reynolds Nina Jones |
| author_sort | Casey R. Williamson |
| collection | DOAJ |
| description | Summary: Podocytes are specialized kidney cells that form the slit diaphragm (SD), an intercellular filtration barrier against plasma protein loss. The SD is subject to significant mechanical strain which can be amplified in disease, leading to podocyte detachment. One key SD protein that might intercept mechanical strain and transmit adhesion signals is nephrin, although its influence on podocyte force transmission remains uncharacterized. Using immunoblotting and elastic resonator interference stress microscopy (ERISM), we demonstrate that nephrin clustering induces rapid podocyte force transmission and adhesion protein activation (paxillin, FAK, and p130Cas), which require nephrin tyrosine phosphorylation at its three YDxV motifs. Furthermore, using a model of diabetic nephropathy to amplify mechanical stress in vivo, we show that abolishing phosphorylation at YDxV tyrosines leads to exacerbated proteinuria, glomerular hypertrophy, and podocyte detachment. Altogether, this study links nephrin phosphorylation with force transmission, which is likely critical to maintaining podocyte adhesion during many renal pathologies. |
| format | Article |
| id | doaj-art-e09f8c5072d44e1b9b95ce80d5c9af46 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-e09f8c5072d44e1b9b95ce80d5c9af462025-08-20T03:13:00ZengElsevieriScience2589-00422025-06-0128611267310.1016/j.isci.2025.112673Reduced nephrin tyrosine phosphorylation impairs podocyte force transmission and accelerates detachment in diseaseCasey R. Williamson0Claire E. Martin1J. Dinesh Kumar2Peihua Lu3Laura A. New4Alice Y. Wang5Nils M. Kronenberg6Malte C. Gather7Paul A. Reynolds8Nina Jones9Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, CanadaDepartment of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, CanadaSUPA, School of Physics and Astronomy, University of St. Andrews, KY16 9SS St. Andrews, UK; Biomedical Sciences Research Complex, University of St. Andrews, KY16 9ST St. Andrews, UKDepartment of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, CanadaDepartment of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, CanadaDepartment of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, CanadaSUPA, School of Physics and Astronomy, University of St. Andrews, KY16 9SS St. Andrews, UK; Biomedical Sciences Research Complex, University of St. Andrews, KY16 9ST St. Andrews, UK; Department of Chemistry, Humboldt Centre for Nano- and Biophotonics, University of Cologne, 50939 Cologne, GermanySUPA, School of Physics and Astronomy, University of St. Andrews, KY16 9SS St. Andrews, UK; Biomedical Sciences Research Complex, University of St. Andrews, KY16 9ST St. Andrews, UK; Department of Chemistry, Humboldt Centre for Nano- and Biophotonics, University of Cologne, 50939 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Disease (CECAD), University of Cologne, 50931 Cologne, GermanyBiomedical Sciences Research Complex, University of St. Andrews, KY16 9ST St. Andrews, UK; School of Medicine, University of St. Andrews, KY16 9TF St. Andrews, UKDepartment of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada; Corresponding authorSummary: Podocytes are specialized kidney cells that form the slit diaphragm (SD), an intercellular filtration barrier against plasma protein loss. The SD is subject to significant mechanical strain which can be amplified in disease, leading to podocyte detachment. One key SD protein that might intercept mechanical strain and transmit adhesion signals is nephrin, although its influence on podocyte force transmission remains uncharacterized. Using immunoblotting and elastic resonator interference stress microscopy (ERISM), we demonstrate that nephrin clustering induces rapid podocyte force transmission and adhesion protein activation (paxillin, FAK, and p130Cas), which require nephrin tyrosine phosphorylation at its three YDxV motifs. Furthermore, using a model of diabetic nephropathy to amplify mechanical stress in vivo, we show that abolishing phosphorylation at YDxV tyrosines leads to exacerbated proteinuria, glomerular hypertrophy, and podocyte detachment. Altogether, this study links nephrin phosphorylation with force transmission, which is likely critical to maintaining podocyte adhesion during many renal pathologies.http://www.sciencedirect.com/science/article/pii/S2589004225009344BiochemistryCell biologySpecialized functions of cellsBiomechanics |
| spellingShingle | Casey R. Williamson Claire E. Martin J. Dinesh Kumar Peihua Lu Laura A. New Alice Y. Wang Nils M. Kronenberg Malte C. Gather Paul A. Reynolds Nina Jones Reduced nephrin tyrosine phosphorylation impairs podocyte force transmission and accelerates detachment in disease iScience Biochemistry Cell biology Specialized functions of cells Biomechanics |
| title | Reduced nephrin tyrosine phosphorylation impairs podocyte force transmission and accelerates detachment in disease |
| title_full | Reduced nephrin tyrosine phosphorylation impairs podocyte force transmission and accelerates detachment in disease |
| title_fullStr | Reduced nephrin tyrosine phosphorylation impairs podocyte force transmission and accelerates detachment in disease |
| title_full_unstemmed | Reduced nephrin tyrosine phosphorylation impairs podocyte force transmission and accelerates detachment in disease |
| title_short | Reduced nephrin tyrosine phosphorylation impairs podocyte force transmission and accelerates detachment in disease |
| title_sort | reduced nephrin tyrosine phosphorylation impairs podocyte force transmission and accelerates detachment in disease |
| topic | Biochemistry Cell biology Specialized functions of cells Biomechanics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225009344 |
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