Journal Article

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

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

2025

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 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