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Published on: May 9, 2025
CXCL6 Orchestrates Macrophage-Driven Inflammation in Diabetic Kidney Disease and Represents a Druggable Target
Yuebo Huang1, Yuxiang Sun1, Dandan Guo1
1Nephrology Division, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Introduction:
Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease and is increasingly recognized to involve early and progressive tubulointerstitial injury. However, the key molecular drivers of this process and their therapeutic potential remain poorly defined.
Methods:
We conducted an integrative analysis of three DKD transcriptomic datasets using weighted gene correlation network analysis and differential expression analysis, followed by single-cell RNA sequencing to localize candidate genes to specific renal cell types. Functional validation was performed using in vitro assays in HK-2 and THP-1 cells, in vivo DKD mouse models, and patient kidney tissue. A virtual screening approach was applied to identify candidate inhibitors.
Results:
We identified CXCL6, a C-X-C motif chemokine, as a central hub gene selectively upregulated in tubular epithelial cells of DKD kidneys. Urinary CXCL6 levels strongly correlated with markers of renal dysfunction. Mechanistically, high-glucose-induced CXCL6 expression in tubular cells, promoting macrophage recruitment, polarization toward a pro-inflammatory phenotype, and increased cytokine release. Through virtual screening, we identified salvianolic acid B (Sal-B) as a putative CXCL6 inhibitor. Sal-B treatment suppressed CXCL6 secretion, macrophage infiltration, and inflammatory cytokine production in vitro.
Conclusion:
Our study uncovers CXCL6 as a key mediator of tubulointerstitial inflammation in DKD, linking tubular injury to immune cell recruitment and cytokine-driven damage. Furthermore, we identify Sal-B as a promising therapeutic candidate targeting this newly characterized pathway, offering potential for diagnostic and therapeutic advancement in DKD.
Insights
Diabetic kidney disease involves tubulointerstitial injury. We found CXCL6 drives inflammation by recruiting macrophages, and salvianolic acid B (Sal-B) may treat this by inhibiting CXCL6.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Diabetic kidney disease (DKD) is a major cause of kidney failure.
- Tubulointerstitial injury is a key feature of DKD progression.
- Molecular drivers of DKD tubulointerstitial injury are not fully understood.
Purpose of the Study:
- Identify molecular drivers of DKD tubulointerstitial injury.
- Investigate the therapeutic potential of targeting identified pathways.
Main Methods:
- Integrative analysis of transcriptomic datasets.
- Single-cell RNA sequencing to localize genes.
- In vitro and in vivo functional validation.
- Virtual screening for therapeutic inhibitors.
Main Results:
- CXCL6 identified as a central hub gene upregulated in DKD tubular cells.
- Urinary CXCL6 correlates with renal dysfunction.
- High glucose induces CXCL6, promoting pro-inflammatory macrophage recruitment.
- Salvianolic acid B (Sal-B) identified as a CXCL6 inhibitor.
- Sal-B suppressed CXCL6, macrophage infiltration, and inflammation in vitro.
Conclusions:
- CXCL6 mediates tubulointerstitial inflammation in DKD.
- CXCL6 links tubular injury to immune cell recruitment and damage.
- Sal-B is a promising therapeutic candidate for DKD targeting the CXCL6 pathway.
