Uromodulin promotes immune zonation and inhibits alternative inflammasome-mediated activation of immune-to-collecting duct inflammatory signaling in early acute kidney injury
Year: 2026
Type: preprint
Abstract: Uromodulin, a protein made uniquely by the kidney, is protective against acute kidney injury. An integrated transcriptomic and multiplexed spatial protein imaging was used to uncover early cellular and molecular pathophysiological mechanisms following murine kidney ischemia and reperfusion injury (IRI) and better define the role of Uromodulin at the early stage of injury. Six hours following IRI, there was a pan-nephronal transcriptomic response with activation of common pathways but also unique gene expression signatures for each nephron segment. Cell-cell communications and epithelial-immune spatial interactions most prominently involved thick ascending limbs and distal nephron segments with distinct immune zonation in the inner stripe of the outer medulla. Uromodulin deficiency swayed the tubular transcriptomic signatures towards more severe injury and inflammation with altered macrophage communication. Uromodulin deficiency also caused partial loss of immune zonation and a shift towards broader epithelial-immune interactions in the outer stripe and cortex. Uromodulin inhibited activation of the Nlrc4- dependent alternative inflammasome pathway in macrophages, where the production of IL-1β predominantly targets other immune and collecting duct (CD) cells. Indeed, Uromodulin deficiency induced the expression of CD8 in CD cells which acquire a proinflammatory phenotype linked to spatial niches containing immune cells. The presence of CD8 + CD cells was validated in human kidney biopsies. In conclusion, our findings support a role for Uromodulin in spatially confining the immune system around TAL cells in the inner stripe away from the vulnerable outer stripe in early injury. Uromodulin also inhibits the inflammasome-mediated macrophage-epithelial crosstalk that could induce collecting duct cells towards more inflammatory signaling.
Language: English
Topic: Acute Kidney Injury Research
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Harvard Chronic Kidney Disease Research Biopsy Center, Understanding the Function of Tamm-Horsfall Protein in Acute kidney Injury., Multidimensional cellular interrogation of the kidney in AKI and CKD, Phenotyping REnal Cases In Sepsis and surgery for Early Acute Kidney Injury (PReCISE AKI), 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), Integrated spatial interrogation of cellular and molecular signatures of human kidney disease, Single cell multiomic and spatial atlas of acute and chronic kidney injury, University of Illinois at Chicago KPMP CKD Recruitment Site, Central Hub for Kidney Precision Medicine, Indiana Center for Advanced Renal Microscopy and Molecular Imaging, Multimodal Imaging Mass Spectrometry and Spatial Omics for the Human Kidney, The protective role of kidney-derived Tamm Horsfall protein (Uromodulin) in sepsis, Boston Chronic Kidney Disease Research Biopsy Center, Kidney Precision Medicine Project - Patient Engagement, Spatial Multi-Omics to Profile Metabolic Pathways for Kidney Disease, Spatial Mapping of Proteomic and Transcriptional Signatures in Kidney Disease
OpenAlex ID: W7133208670