Parallel metabolomic and transcriptomic profiling reveals the cytotoxic mechanism of protein-bound uremic toxin p-cresol sulfate via disruption of glutathione and glycerophospholipid metabolism in MC3T3-E1 osteoblasts.

BACKGROUND

Chronic kidney disease-mineral bone disorder (CKD-MBD), a common complication of chronic kidney disease (CKD), leads to vascular calcification, osteoporosis, and electrolyte disturbances, impacting patient survival and quality of life. Conventional dialysis poorly removes protein-bound uremic toxins like p-cresyl sulfate (PCS), which are linked to CKD-MBD. This study combined metabolomics and transcriptomics to explore PCS's cytotoxic mechanisms in CKD-MBD for better clinical management.

METHODS

Using MC3T3-E1 osteoblasts treated with or without PCS, metabolic changes were analyzed via ultra-high performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS), and transcriptomic changes through RNA sequencing (RNA-seq).

RESULTS

UHPLC-QTOF/MS identified 74 significantly altered metabolites and 15 disrupted metabolic pathways in PCS-treated osteoblasts. RNA-seq revealed 3,679 differentially expressed genes, with pathway analysis indicating significant disruptions in glutathione and glycerophospholipid metabolism, and alterations in cell apoptosis, cell cycle, and DNA repair processes.

CONCLUSIONS

Parallel metabolomics and transcriptomics profiling showed PCS-induced disruptions in glutathione and glycerophospholipid pathways are central to cellular metabolic dysfunction in CKD-MBD. These insights highlight the potential of multi-omics to elucidate uremic toxin pathophysiology, providing a foundation for improved CKD-MBD management.