Spatial proteomics identifies altered thick ascending limb cells as drivers of kidney disease through uromodulin retention
Year: 2026
Type: preprint
Abstract: Chronic kidney disease (CKD) is increasingly prevalent and is a leading cause of mortality. Recent transcriptomic studies have identified the persistence of injury-induced renal tubular epithelial cell states, yet the cell populations that drive CKD remain unresolved. Uromodulin (UMOD) is the most abundant urinary secreted protein expressed exclusively in thick ascending limb (TAL) epithelial cells in the kidney. UMOD is strongly associated with CKD risk in genome-wide association studies, suggesting a broader, yet unexplored role of UMOD and TAL cells in CKD pathogenesis. Here, using spatial proteomics, we identified an injury-induced TAL cell state marked by intracellular UMOD accumulation. Spatially resolved multimodal integration revealed that UMOD accumulation occurred without transcriptional upregulation. Impaired urinary UMOD secretion further supported pathological intracellular retention. These altered TAL cells with UMOD retention exhibited inflammatory signaling, formed profibrotic niches enriched with M2-like macrophages across renal compartments, and were associated with CKD progression in multiple experimental models. Reducing the burden of UMOD retention diminished altered TAL cells and their profibrotic microenvironments, and attenuated CKD development. A similar altered TAL state was identified in human kidney disease and was associated with worse kidney function. Together, we identify pathological UMOD retention and altered TAL cells as key drivers of CKD development and potential therapeutic targets. This study also highlights that protein-level alterations can redefine disease-associated cell states beyond transcript profiling.
Authors: Azuma Nanamatsu, George J. Rhodes, William S. Bowen, Angela R. Sabo, Shehnaz Khan, Mahla Asghari, Dillen L. Wischmeier, Daria Barwinska, Takashi Kudo, Azusa Tomioka, Hiroaki Sakaue, Atsushi Kuno, Ana C. Ricardo, James P. Lash, Katherine R. Tuttle, Pierre C. Dagher, Jonathan Himmelfarb, Kaice A. LaFavers, Luca Rampoldi, Tarek M. El-Achkar
Institutions: Indiana University School of Medicine, University of Tsukuba, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, University of Illinois Chicago, University of Washington, Icahn School of Medicine at Mount Sinai, Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele, IRCCS San Raffaele Roma, Richard L. Roudebush VA Medical Center
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Harvard Chronic Kidney Disease Research Biopsy Center, Multidimensional cellular interrogation of the kidney in AKI and CKD, Phenotyping REnal Cases In Sepsis and surgery for Early Acute Kidney Injury (PReCISE AKI), Intracellular retention of uromodulin as a common pathomechanism in chronic kidney disease, Kidney Precision Medicine Program (KPMP): Columbia AKI Recruitment Site, Spatial Elucidation of Human Acute Kidney Injury and Chronic Kidney Disease using Imaging Mass Cytometry, PREcision Medicine through IntErrogation of Rna in the kidnEy (PREMIERE), Minnesota Precision Medicine CKD & Resilient Diabetes Recruiting Site: Engagement, Enrollment & Ethics, Integrated spatial interrogation of cellular and molecular signatures of human kidney disease, Single cell multiomic and spatial atlas of acute and chronic kidney injury, Mount Sinai Health System Kidney Precision Medicine Project, University of Illinois at Chicago KPMP CKD Recruitment Site, AKI Matched Phenotype Linked Evaluation with Tissue (AMPLE-Tissue), Central Hub for Kidney Precision Medicine, Multimodal Imaging Mass Spectrometry and Spatial Omics for the Human Kidney, Boston Chronic Kidney Disease Research Biopsy Center, Cleveland Precision Medicine Chronic Kidney Disease Cohort, Kidney Precision Medicine Project - Patient Engagement, KPMP Kidney Mapping and Atlas Project (KMAP), Geographic and Environmental Health Equity in Kidney Precision Medicine, Spatial Multi-Omics to Profile Metabolic Pathways for Kidney Disease, Spatial Mapping of Proteomic and Transcriptional Signatures in Kidney Disease
OpenAlex ID: W7221541739