Metabolic regulation of uridine in diabetic kidney disease and its pharmacological modulation by schisandrin B.

BACKGROUND: Diabetic kidney disease (DKD) has become a leading cause of end-stage renal disease globally. Metabolic dysregulation is a core characteristic of DKD, with metabolites acting as both disease biomarkers and drivers of pathological progression. Thus, exploring new therapeutic strategies centered on metabolism holds promise for the treatment of DKD. PURPOSE: This study aimed to characterize spatially resolved metabolic reprogramming in DKD, elucidate the mechanisms of uridine-mediated renoprotection, and identify therapeutic compounds targeting uridine metabolism. METHODS: Clinical metabolomics of 228 participants (62 healthy individuals and 166 DKD patients) and desorption electrospray ionization mass spectrometry imaging (DESI-MSI) were integrated to profile metabolic alterations in DKD. DKD mouse models were used to evaluate the effects of uridine supplementation. Multi-omics analysis (transcriptomics, proteomics, and subcellular mapping) deciphered molecular mechanisms. High-throughput screening of 1880 natural products was performed to identify modulators of enzymes involved in uridine metabolism. RESULTS: DESI-MSI revealed a pronounced disruption of pyrimidine metabolism characterized by a marked reduction in renal cortical uridine levels in DKD. Uridine supplementation significantly ameliorated glucolipid metabolic disturbances and renal injury in DKD mice. We identified a dual-synergistic mechanism by which uridine exerts renoprotective effects: restoring mitochondrial bioenergetics while inhibiting the EGR1-P300-ETS1 signaling axis. High-throughput screening identified schisandrin B (SchB) as a potential modulator of uridine metabolism, with binding free energies of -8.5 and -8.2 kcal/mol to DHODH and UMPS, respectively. SchB increased uridine levels and ameliorated DKD pathology via the same mechanism. CONCLUSION: The findings highlight uridine as a key metabolic regulator in DKD and offer a novel precision treatment strategy targeting metabolic modulation, demonstrating promising potential for the treatment of DKD.