Nafamostat Mesylate Protects Against Acute Renal Ischemia-Reperfusion Injury by Alleviating Mitochondrial Dysfunction, Inhibiting Ferroptosis, and Regulating Proximal Tubular Cells: A Multi-Omics Analysis.

OBJECTIVE

The present study aims to explore the role of nafamostat mesylate (NM) in ischemia-reperfusion (I/R)-induced acute kidney injury (AKI).

METHODS

Twenty-one male rats were randomly divided into three groups: sham, I/R, and I/R + NM groups. Acute renal I/R injury models were created in the I/R and I/R + NM groups by right nephrectomy and clamping the left renal pedicle for 45 min. Rats in the I/R + NM group were intraperitoneally injected with 0.75 mg/kg of NM before modeling. Blood and kidney specimens were collected at 24 h after model establishment. RNA sequencing (RNA-seq), KEGG and GO enrichment analyses, and single-cell sequencing were carried out to investigate the related mechanisms.

RESULTS

The pretreatment with NM improved renal function, reduced mitochondrial damage, suppressed the accumulation of reactive oxygen species, and inhibited ferroptosis. The RNA-seq indicated that NM induced protection by upregulating fatty acids, inhibiting inflammation, and promoting DNA repair. Proximal tubular cells were mainly affected.

CONCLUSION

NM protects against AKI by reducing reactive oxygen species, upregulating fatty acids, and regulating ferroptosis signaling pathways in proximal tubular cells.