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Proximal tubular epithelial cells (PTECs) injury is a driving force toward chronic kidney disease (CKD) progression. However, the characteristics of injured PTECs during CKD pathogenesis and their mechanisms of coordination with specific interstitial cells to promote disease progression require further elucidation. In this study, CKD mouse models were established by administering a 0. 2% adenine-containing diet for 2, 4, and 8 weeks to simulate progressive CKD. Renal injury was assessed through histopathology, serum creatinine (Scr), blood urea nitrogen (BUN), and expression of fibrotic markers. Single-cell RNA sequencing (scRNA-seq) was employed to characterize renal cellular heterogeneity during CKD progression. The results showed that adenine feeding induced renal pathological damage, elevated Scr and BUN levels, and upregulated fibrosis-related markers, with the most severe manifestations observed in CKD8w group. In addition, scRNA-seq identified a distinct injured PTEC subset (PT₅) localized to the S1 segment, which progressively expanded during CKD, exhibited elevated injury markers (C3, Havcr1, Vcam1), and activated pathways linked to inflammation and fibrosis. Cell-cell interaction analysis revealed PT₅ coordinates interstitial remodeling via ligand-receptor pairs: CCL2-CCR2/IL34-CSF1R with macrophages, PDGF-PDGFR with fibroblasts, and CXCL10-CXCR3 with T and NK cells. Furthermore, CKD progression may correlate with expansion of MyofibroblastsTimp1, MacrophagesMmp12, and CD8TeffCcl5 subsets. Our study uncovers PT₅ may be the central orchestrator of CKD progression through multicellular crosstalk, offering novel mechanistic insights and therapeutic targets.
Xu et al. (Mon,) studied this question.