Neutrophil Extracellular Traps Drive Kidney Stone Formation

Introduction: This study aims to explore the contribution of neutrophil extracellular traps (NETs) to kidney stones.

Methods: The microarray data from GSE73680 and bioinformatic analysis were applied to identify differentially expressed genes in patients with kidney stones. A rat model of kidney stones was established through ethylene glycol and ammonium chloride administration. The plasma was collected for examining cf-DNA, DNase I, MPO-DNA, H3Cit and NE. Superoxide dismutase, malondialdehyde, creatinine, blood urea nitrogen, and calcium were examined through biochemical analysis. MPO, H3Cit, and NE in kidney tissues were detected via immunofluorescence staining. Cell apoptosis was evaluated through TUNEL assays. HE, Periodic Acid-Schiff and Von Kossa staining were applied to determine histological structure, calcium deposits and stone formation in the kidneys. Neutrophil elastase inhibitor Sivelestat (SIVE) was administrated for NET suppression in rats.

Results: A total of 403 differentially expressed genes including 270 upregulated and 133 downregulated genes were identified between renal papillary tissues with Randall's plaque and normal tissues. Gene ontology enrichment, KEGG pathway and protein-protein interaction network analysis of these dysregulated genes were performed. Moreover, increased NET markers including cf-DNA, DNase I, MPO-DNA, H3Cit and NE and calcium deposits were observed in patients with kidney stones. Subsequently, we established a rat model of kidney stones. We found that NET formation was significantly elevated in kidney stone rats, and renal tubular injury and apoptotic cells were enhanced as kidney stones developed. Strikingly, we found that suppression of NETs via SIVE could significantly reduce calcium deposits and apoptotic cells and alleviate tubular injury, thus improving kidney function.

Conclusion: NETs drive the formation of kidney stones, thus aggravating kidney injury. Our study identifies NETs as a potential diagnostic and therapeutic biomarker for nephrolithiasis.