Aims

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, in which chronic inflammation and mitochondrial metabolic dysfunction are central pathogenic drivers. This study aimed to determine whether these molecular programs are evolutionarily conserved and coordinated as a unified immunometabolic network across vertebrate species.

Methods

We analyzed publicly available transcriptomic datasets from 73 kidney samples from three vertebrate species: two independent human cohorts (n=43), mouse kidney samples including a Pink1⁻/⁻ model (n=18), and zebrafish kidney samples (n=12). Differentially expressed genes (adjusted P < 0.05, |log₂FC| > 1) were identified within each species, followed by ortholog mapping using biomaRt, GO/KEGG enrichment analyses, STRING-based protein–protein interaction analysis, and cross-module correlation analysis.

Results

Cross-species pathway analysis consistently demonstrated activation of inflammatory pathways, including innate and extracellular immune responses, antigen presentation, unfolded protein response, and integrated stress response, together with widespread dysregulation of mitochondrial oxidative phosphorylation and energy metabolism. Ortholog mapping confirmed that these transcriptional programs were conserved across human, mouse, and zebrafish. Protein–protein interaction analysis of 64 human–mouse, 236 human–zebrafish, and 80 mouse–zebrafish overlapping DEGs identified 23 interaction clusters, of which 9 functional clusters were annotated, including inflammatory response, morphogenesis, vascular regulation, and metabolic processes. Integration of inflammatory and metabolic modules further demonstrated coordinated interactions between immune activation and mitochondrial metabolic remodeling, defining a conserved immunometabolic network shared across vertebrate DKD.

Conclusions

Cross-species transcriptomic integration reveals that inflammatory activation and mitochondrial metabolic remodeling are functionally coordinated as a conserved immunometabolic network in vertebrate DKD, rather than representing independent molecular alterations. These findings establish an evolutionarily conserved framework for DKD pathogenesis and suggest that co-targeting innate immune activation and mitochondrial energy sensing may offer mechanistic leverage for translational intervention.