Integration of transcriptomics and metabolomics reveals the molecular mechanisms underlying the effect of nafamostat mesylate on rhabdomyolysis-induced acute kidney injury

Abstract

Objective: To investigate the role and mechanisms of action of nafamostat mesylate (NM) in rhabdomyolysis-induced acute kidney injury (RIAKI).Methods: RIAKI rats were assigned into control group (CN), RIAKI group (RM), and NM intervention group (NM). Inflammatory cytokines and proenkephalin a 119–159 (PENKID) were assessed. Cell apoptosis and glutathione peroxidase-4 (GPX4) were detected using TUNEL assay and immunohistochemical staining. Mitochondrial membrane potential (MMP) was detected by JC-1 dye. The expression of genes and metabolites after NM intervention was profiled using transcriptomic and metabolomic analysis. The differentially expressed genes (DEGs) were validated using qPCR. The KEGG and conjoint analysis of transcriptome and metabolome were used to analyze the enriched pathways and differential metabolites. The transcription factors were identified based on the animal TFDB 3.0 database.Results: Serum creatinine, blood urea nitrogen, and PENKID were remarkably higher in the RM group and lower in the NM group compared to the CN group. Pro-inflammatory cytokines increased in the RM group and notably decreased following NM treatment compared to the CN group. Tubular pathological damages were markedly attenuated and renal cell apoptosis was reduced significantly in the NM group compared to the RM group. The expression of GPX4 was lower in the RM group compared to the CN group, and it increased significantly after NM treatment. A total of 294 DEGs were identified in the RM group compared with the NM group, of which 192 signaling pathways were enriched, and glutathione metabolism, IL-17 signaling, and ferroptosis-related pathways were the top-ranking pathways. The transcriptional levels of Anpep, Gclc, Ggt1, Mgst2, Cxcl13, Rgn, and Akr1c1 were significantly different between the NM and RM group. Gclc was the key gene contributing to NM-mediated renal protection in RIAKI. Five hundred and five DEGs were annotated. Compared with the RM group, most of the upregulated DEGs in the NM group belonged to Glutathione metabolism, whereas most of the downregulated DEGs were related to the transcription factor Cytokine-cytokine receptor interaction.Conclusion: NM protects the kidneys against RIAKI, which is mainly associated with NM mediated regulation of glutathione metabolism, inflammatory response, ferroptosis-related pathways, and the related key DEGs. Targeting these DEGs might emerge as a potential molecular therapy for RIAKI.

Molecular Mechanisms of Ferroptosis and Their Involvement in Acute Kidney Injury

“… 78 It was found that nalmestat mesylate could inhibit the development of RM-AKI by mediating ferroptosis pathways such as glutathione metabolism and ferritin metabolism, as well as regulating the inflammatory response and associated expression of key differentially expressed genes, and it was suggested that nalmestat mesylate could be a potential target drug for the targeted treatment of RM-AKI. 79 …”

Elucidating ascorbate and aldarate metabolism pathway characteristics via integration of untargeted metabolomics and transcriptomics of the kidney of high-fat diet-fed obese mice

“…Data integration often involves aligning data with corresponding Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Guo et al [22] successfully utilized combined transcriptomic and metabolomic analyses to understand the molecular mechanisms underlying the effects of drugs on acute kidney injury. Overall, integrating multiple omics data can help identify previously unrecognized interrelationships between different biological or molecular pathways.…”