Multiomic analysis of human kidney disease identifies a tractable inflammatory and pro-fibrotic tubular cell phenotype

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 and Bryan R. Conway ()
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Maximilian Reck: University of Edinburgh
David P. Baird: University of Edinburgh
Stefan Veizades: University of Edinburgh
Callum Sutherland: University of Edinburgh
Rachel M. B. Bell: University of Edinburgh
Heeyoun Hur: University of Edinburgh
Carolynn Cairns: University of Edinburgh
Piotr P. Janas: University of Edinburgh
Ross Campbell: University of Edinburgh
Andy Nam: Bruker Spatial Biology
Wei Yang: Bruker Spatial Biology
Nathan Schurman: Bruker Spatial Biology
Claire Williams: Bruker Spatial Biology
Eoin O’Sullivan: University of Queensland
Meryam Beniazza: University of Edinburgh
Andrea Corsinotti: University of Edinburgh
Christopher Bellamy: University of Edinburgh
Jeremy Hughes: University of Edinburgh
Alexander Laird: University of Edinburgh
Laura Denby: University of Edinburgh
Tamir Chandra: University of Edinburgh
David A. Ferenbach: University of Edinburgh
Bryan R. Conway: University of Edinburgh

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59997-4

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