Single-cell Stereo-seq reveals regulatory mechanisms driving regeneration of injured proximal tubules during AKI.

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in renal function. Proximal tubule (PT) cells play a central role in AKI. However, the specific populations and states of PT that facilitate repair remain poorly understood. Here, we combine spatial enhanced resolution omics sequencing with single-nucleus RNA sequencing to profile kidney transcriptomes during AKI. We identify an ischemia-reperfusion injury-induced PT subtype, termed proliferative PT, that likely initiates renal regeneration and exhibits a gene expression enriched in mitosis and metabolic processes. Acsm2 is expressed in proliferative PT and is associated with cell cycle progression. Functional studies reveal the protective role of Acsm2 via deficiency and overexpressing mice. Finally, we identify a subcluster of Fibroblast (FIB_C2) that participates in PT repair through cell-cell communication with proliferative PT. Our study provides an integrated high-resolution spatiotemporal atlas of AKI and reveals the important role of Acsm2 in kidney regeneration.