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

Abstract

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.