Multiomic analysis of human kidney disease identifies a tractable inflammatory and pro-fibrotic tubular cell phenotype
Abstract Maladaptive proximal tubular (PT) epithelial cells have been implicated in progression of chronic kidney disease (CKD), however the complexity of epithelial cell states within the fibrotic niche remains incompletely understood. Hence, we integrated snRNA and ATAC-seq with high-plex single-c...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59997-4 |
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| author | Maximilian Reck David P. Baird Stefan Veizades Callum Sutherland Rachel M. B. Bell Heeyoun Hur Carolynn Cairns Piotr P. Janas Ross Campbell Andy Nam Wei Yang Nathan Schurman Claire Williams Eoin O’Sullivan Meryam Beniazza Andrea Corsinotti Christopher Bellamy Jeremy Hughes Alexander Laird Laura Denby Tamir Chandra David A. Ferenbach Bryan R. Conway |
| author_facet | Maximilian Reck David P. Baird Stefan Veizades Callum Sutherland Rachel M. B. Bell Heeyoun Hur Carolynn Cairns Piotr P. Janas Ross Campbell Andy Nam Wei Yang Nathan Schurman Claire Williams Eoin O’Sullivan Meryam Beniazza Andrea Corsinotti Christopher Bellamy Jeremy Hughes Alexander Laird Laura Denby Tamir Chandra David A. Ferenbach Bryan R. Conway |
| author_sort | Maximilian Reck |
| collection | DOAJ |
| description | Abstract Maladaptive proximal tubular (PT) epithelial cells have been implicated in progression of chronic kidney disease (CKD), however the complexity of epithelial cell states within the fibrotic niche remains incompletely understood. Hence, we integrated snRNA and ATAC-seq with high-plex single-cell molecular imaging to generate a spatially-revolved multiomic atlas of human kidney disease. We demonstrate that in injured kidneys, a subset of HAVCR1 + VCAM1 + PT cells acquired an inflammatory phenotype, upregulating genes encoding chemokines, pro-fibrotic and senescence-associated proteins and adhesion molecules including ICAM1. Spatial transcriptomic and multiplex-immunofluorescence determined that specifically these VCAM1+ICAM1+ inflammatory PT cells localised to the fibrotic niche. Ligand-receptor analysis highlighted paracrine signaling from inflammatory PT cells mediating leucocyte recruitment and myofibroblast activation. Loss of HNF4α and activation of NF-κβ and AP-1 transcription factors epigenetically imprinted the inflammatory phenotype. Targeting inflammatory tubular cells by administering an AP-1 inhibitor or senolytic agent ameliorated inflammation and fibrosis in murine models of kidney injury, hence these cells may be a tractable target in CKD. |
| format | Article |
| id | doaj-art-b9a4b8406f164946a8482841d8dfc504 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b9a4b8406f164946a8482841d8dfc5042025-08-20T03:08:43ZengNature PortfolioNature Communications2041-17232025-05-0116112310.1038/s41467-025-59997-4Multiomic analysis of human kidney disease identifies a tractable inflammatory and pro-fibrotic tubular cell phenotypeMaximilian Reck0David P. Baird1Stefan Veizades2Callum Sutherland3Rachel M. B. Bell4Heeyoun Hur5Carolynn Cairns6Piotr P. Janas7Ross Campbell8Andy Nam9Wei Yang10Nathan Schurman11Claire Williams12Eoin O’Sullivan13Meryam Beniazza14Andrea Corsinotti15Christopher Bellamy16Jeremy Hughes17Alexander Laird18Laura Denby19Tamir Chandra20David A. Ferenbach21Bryan R. Conway22Centre for Cardiovascular Science, University of EdinburghCentre for Inflammation Research, University of EdinburghCentre for Cardiovascular Science, University of EdinburghCentre for Cardiovascular Science, University of EdinburghCentre for Cardiovascular Science, University of EdinburghCentre for Cardiovascular Science, University of EdinburghCentre for Cardiovascular Science, University of EdinburghCentre for Inflammation Research, University of EdinburghCentre for Inflammation Research, University of EdinburghBruker Spatial BiologyBruker Spatial BiologyBruker Spatial BiologyBruker Spatial BiologyInstitute of Molecular Bioscience, University of QueenslandInstitute for Regeneration and Repair, University of EdinburghInstitute for Regeneration and Repair, University of EdinburghCentre for Inflammation Research, University of EdinburghCentre for Inflammation Research, University of EdinburghInstitute of Genetics and Cancer, University of EdinburghCentre for Cardiovascular Science, University of EdinburghMRC Human Genetics Unit, University of EdinburghCentre for Inflammation Research, University of EdinburghCentre for Cardiovascular Science, University of EdinburghAbstract Maladaptive proximal tubular (PT) epithelial cells have been implicated in progression of chronic kidney disease (CKD), however the complexity of epithelial cell states within the fibrotic niche remains incompletely understood. Hence, we integrated snRNA and ATAC-seq with high-plex single-cell molecular imaging to generate a spatially-revolved multiomic atlas of human kidney disease. We demonstrate that in injured kidneys, a subset of HAVCR1 + VCAM1 + PT cells acquired an inflammatory phenotype, upregulating genes encoding chemokines, pro-fibrotic and senescence-associated proteins and adhesion molecules including ICAM1. Spatial transcriptomic and multiplex-immunofluorescence determined that specifically these VCAM1+ICAM1+ inflammatory PT cells localised to the fibrotic niche. Ligand-receptor analysis highlighted paracrine signaling from inflammatory PT cells mediating leucocyte recruitment and myofibroblast activation. Loss of HNF4α and activation of NF-κβ and AP-1 transcription factors epigenetically imprinted the inflammatory phenotype. Targeting inflammatory tubular cells by administering an AP-1 inhibitor or senolytic agent ameliorated inflammation and fibrosis in murine models of kidney injury, hence these cells may be a tractable target in CKD.https://doi.org/10.1038/s41467-025-59997-4 |
| spellingShingle | Maximilian Reck David P. Baird Stefan Veizades Callum Sutherland Rachel M. B. Bell Heeyoun Hur Carolynn Cairns Piotr P. Janas Ross Campbell Andy Nam Wei Yang Nathan Schurman Claire Williams Eoin O’Sullivan Meryam Beniazza Andrea Corsinotti Christopher Bellamy Jeremy Hughes Alexander Laird Laura Denby Tamir Chandra David A. Ferenbach Bryan R. Conway Multiomic analysis of human kidney disease identifies a tractable inflammatory and pro-fibrotic tubular cell phenotype Nature Communications |
| title | Multiomic analysis of human kidney disease identifies a tractable inflammatory and pro-fibrotic tubular cell phenotype |
| title_full | Multiomic analysis of human kidney disease identifies a tractable inflammatory and pro-fibrotic tubular cell phenotype |
| title_fullStr | Multiomic analysis of human kidney disease identifies a tractable inflammatory and pro-fibrotic tubular cell phenotype |
| title_full_unstemmed | Multiomic analysis of human kidney disease identifies a tractable inflammatory and pro-fibrotic tubular cell phenotype |
| title_short | Multiomic analysis of human kidney disease identifies a tractable inflammatory and pro-fibrotic tubular cell phenotype |
| title_sort | multiomic analysis of human kidney disease identifies a tractable inflammatory and pro fibrotic tubular cell phenotype |
| url | https://doi.org/10.1038/s41467-025-59997-4 |
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