Spatial proteomics identifies altered thick ascending limb cells as drivers of kidney disease through uromodulin retention
- 1Indiana University School of Medicine
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.
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BibTeX
@misc{nanamatsu2026spatial,
title = {{Spatial proteomics identifies altered thick ascending limb cells as drivers of kidney disease through uromodulin retention}},
author = {A. Nanamatsu and G. J. Rhodes and W. S. Bowen and A. R. Sabo and S. Khan and M. Asghari and D. L. Wischmeier and D. Barwinska and T. Kudo and A. Tomioka and H. Sakaue and A. Kuno and A. C. Ricardo and J. P. Lash and K. R. Tuttle and P. C. Dagher and J. Himmelfarb and K. A. LaFavers and L. Rampoldi and T. M. El-Achkar},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.756985},
url = {https://www.biorxiv.org/content/10.64898/2026.10.09.756985v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Spatial proteomics identifies altered thick ascending limb cells as drivers of kidney disease through uromodulin retention
AU - A. Nanamatsu
AU - G. J. Rhodes
AU - W. S. Bowen
AU - A. R. Sabo
AU - S. Khan
AU - M. Asghari
AU - D. L. Wischmeier
AU - D. Barwinska
AU - T. Kudo
AU - A. Tomioka
AU - H. Sakaue
AU - A. Kuno
AU - A. C. Ricardo
AU - J. P. Lash
AU - K. R. Tuttle
AU - P. C. Dagher
AU - J. Himmelfarb
AU - K. A. LaFavers
AU - L. Rampoldi
AU - T. M. El-Achkar
PY - 2026
DA - 2026/10/09
PB - bioRxiv
DO - 10.64898/2026.10.09.756985
UR - https://www.biorxiv.org/content/10.64898/2026.10.09.756985v1
AB - 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.
ER -