Expansion of bone marrow Cxcr5⁺ B cells is associated with renal injury in early-stage diabetic kidney disease: potential implications for B-cell-targeted immunotherapy

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, yet the immune mechanisms contributing to early-stage renal injury remain incompletely understood. This study investigates the association between B-cell dynamics and renal injury in early DKD. Here, we performed single-cell RNA sequencing (scRNA-seq) on bone marrow (BM) and kidneys from 16-week-old db/m and db/db mice, combined with multi-omics data analysis, as well as anti-CD20 antibody-mediated B cell depletion experiments, to characterize B-cell state changes in the context of early-stage DKD. We observed aberrant B-cell differentiation in the BM of DKD mice, with a significantly increased proportion of activated Cxcr5 ⁺ B cells compared to controls. The Cxcl13-Cxcr5 signaling pathway was markedly upregulated in DKD kidneys, with elevated Cxcl13 expression specifically localized to the thick ascending limb (tAL). Cell–cell communication analysis revealed that tAL-B-cell interactions were prominently connected via this axis. Computational perturbation analysis of CXCR5 in mouse and human B cells highlighted its potential association with activation and differentiation signatures. Furthermore, anti-CD20-mediated B-cell depletion significantly attenuated renal injury in DKD mice, and transcriptomic profiling suggested that this protective effect was accompanied by restoration of renal metabolic pathways. Collectively, our findings suggest that expansion of BM Cxcr5 ⁺ B cells is closely associated with renal injury in early-stage DKD, with the CXCL13-CXCR5 axis identified as a potential mediator of B-cell accumulation. B-cell depletion ameliorates renal injury, suggesting that immunomodulation of B cells may represent a promising therapeutic avenue, although direct causal validation requires further experimental investigation.