Neutrophil extracellular traps: a novel contributor to vascular calcification in chronic kidney disease

TL;DR

This study shows that neutrophil extracellular traps (NETs) may contribute to vascular calcification in chronic kidney disease, offering new insights into potential treatments.

Contribution

The study identifies specific NET-related genes and their potential role in vascular calcification in CKD.

Findings

36 NET-related genes were differentially expressed in CKD rodent models.

Mmp12 and Comp were identified as top diagnostic markers with high predictive performance.

NET deposition was confirmed in calcified arteries of rats, linking NET biology to vascular calcification.

Abstract

Among patients with chronic kidney disease (CKD), vascular calcification significantly contributes to cardiovascular health issues, though the underlying molecular mechanisms remain unclear. Recent research highlights neutrophil extracellular traps (NETs) as critical mediators of vascular damage and pro-calcific processes.

We obtained transcriptomic data from the NCBI GEO database for CKD rodent models and identified differentially expressed genes, selected genes using machine learning, functional enrichment, profiling of immune infiltration, transcription factor (TF) activity prediction and drug–gene interaction analysis.

Our analysis revealed 36 NET-related genes with differential expression, and 19 were confirmed by the RobustRankAggreg method. Among them, Mmp12 and Comp emerged as the most consistently selected diagnostic markers across five machine learning algorithms, exhibiting excellent predictive performance (AUC > 0.95). These genes were enriched in neutrophil chemotaxis, ECM remodeling, and PI3K-Akt-mTOR signaling pathways. Immunohistochemistry confirmed NET deposition in calcified arteries of rat, and quantitative PCR and Western blot validated key NRGs expression in CKD rat aortae.

Our results demonstrate that NET-related genes may contribute to CKD-associated vascular calcification in rodent models. Specifically, this work provides evidence for a potential mechanistic link between NET biology and vascular calcification in CKD, thereby offering insights into immune-vascular interactions and raising the possibility of exploring NET-targeted approaches to mitigate vascular damage.

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