Endothelial CXCR2-RAC2 axis contributes to glomerular inflammation and injury in diabetic kidney disease

Abstract Aims Glomerular endothelial dysfunction is a pivotal early event in diabetic kidney disease (DKD), a major cause of end-stage renal disease worldwide. Although the chemokine receptor CXCR2 has been implicated in DKD-associated inflammation, its functional roles within glomerular endothelial cells and the underlying signaling mechanisms remain poorly defined. Materials and methods We first demonstrated that CXCR2 is upregulated in the kidney of patients with DKD and in diabetic mouse models, with glomerular CXCR2 levels correlating with the severity of renal injury in mice. The functional role of CXCR2 was then investigated using diabetic mouse models with endothelial-targeted deletion of Cxcr2 and in glomerular endothelial cells exposed to high glucose and palmitic acid. RNA sequencing was employed to identify RAC2 as a potential downstream effector, the involvement of which was subsequently validated in functional assays. Results Endothelial-targeted deficiency of Cxcr2 ameliorated glomerular damage and suppressed the expression of key inflammatory mediators, including IL-1β, ICAM-1, and VCAM-1, in both in vivo and in vitro settings. Conversely, CXCR2 overexpression exacerbated these pathological features. Unbiased RNA sequencing identified RAC2 as a differentially expressed gene associated with CXCR2 signaling. Crucially, overexpression of RAC2 abrogated the protective effects conferred by CXCR2 silencing, supporting a functional association between RAC2 and CXCR2‑related glomerular endothelial injury. Conclusions Our findings support a CXCR2–RAC2 signaling axis that promotes inflammation and oxidative stress in DKD, revealing a new mechanistic framework and a candidate target for future therapeutic investigations.