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Significance A single acute kidney injury event increases the risk of progression to chronic kidney disease (CKD). Combining single-nucleus RNA sequencing with genetic tracing of injured proximal tubule cells identified a spatially dynamic, evolving injury response following ischemia–reperfusion injury. Failed proximal tubule repair leads to the persistence of a profibrotic, proinflammatoryVcam1 + /Ccl2 + cell type exhibiting a senescence-associated secretory phenotype and a marked transcriptional activation of NF-κB and AP-1 pathway signatures, but no signs of G2 /M cell cycle arrest. Insights from this study can inform strategies to improve renal repair and prevent CKD progression.

Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury