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

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 molec...

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Vydané v:	Nature communications Ročník 16; číslo 1; s. 4745 - 23
Hlavní autori:	Reck, Maximilian, Baird, David P., Veizades, Stefan, Sutherland, Callum, Bell, Rachel M. B., Hur, Heeyoun, Cairns, Carolynn, Janas, Piotr P., Campbell, Ross, Nam, Andy, Yang, Wei, Schurman, Nathan, Williams, Claire, O’Sullivan, Eoin, Beniazza, Meryam, Corsinotti, Andrea, Bellamy, Christopher, Hughes, Jeremy, Laird, Alexander, Denby, Laura, Chandra, Tamir, Ferenbach, David A., Conway, Bryan R.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 22.05.2025 Nature Publishing Group Nature Portfolio
Predmet:	13/51 38/15 38/39 38/91 692/4017 692/4022/1585/104 Activator protein 1 Animal models Animals Chemokines Complexity Disease Models, Animal Epithelial cells Epithelial Cells - metabolism Epithelial Cells - pathology Epithelium Female Fibrosis Genotype & phenotype Hepatitis A Virus Cellular Receptor 1 - genetics Hepatitis A Virus Cellular Receptor 1 - metabolism Humanities and Social Sciences Humans Immunofluorescence Inflammation - genetics Inflammation - metabolism Inflammation - pathology Intercellular adhesion molecule 1 Intercellular Adhesion Molecule-1 - genetics Intercellular Adhesion Molecule-1 - metabolism Kidney diseases Kidney Tubules, Proximal - metabolism Kidney Tubules, Proximal - pathology Kidneys Male Mice Mice, Inbred C57BL multidisciplinary NF-kappa B - metabolism Paracrine signalling Phenotype Phenotypes Renal Insufficiency, Chronic - genetics Renal Insufficiency, Chronic - metabolism Renal Insufficiency, Chronic - pathology Science Science (multidisciplinary) Senescence snRNA Transcription Factor AP-1 - antagonists & inhibitors Transcription Factor AP-1 - metabolism Transcription factors Transcriptomics Vascular Cell Adhesion Molecule-1 - genetics Vascular Cell Adhesion Molecule-1 - metabolism
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. The complexity of epithelial cell states in the fibrotic niche in the context of chronic kidney disease remains incompletely understood. Here the authors integrate snRNA and ATAC-seq with high-plex single-cell molecular imaging to generate a spatially-revolved multiomic atlas of human kidney disease.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-025-59997-4