Celastrol, a bioactive compound from Tripterygium wilfordii, exerts renoprotective effects by modulating the gut-kidney axis and PPAR signaling in a mouse model of diabetic kidney disease

Objective: To investigate the mechanisms underlying the renoprotective effects of celastrol, a bioactive compound extracted from the traditional Chinese medicinal plant Tripterygium wilfordii in diabetic kidney disease (DKD). Methods: We established a DKD model using db/db mice and investigated the protective mechanisms of celastrol against DKD progression using integrated analysis of 16S rRNA sequencing and transcriptome analysis. We evaluated colon tissue damage using hematoxylin and eosin and immunofluorescence staining. In addition, 16S rRNA sequencing and transcriptomic analyses were performed to explore the potential mechanisms of celastrol. Immunofluorescence staining, Western blotting and real-time quantitative polymerase chain reaction analysis were performed to confirm the PPAR signaling pathway related proteins in kidney tissues. Results: Celastrol alleviated colon injury and increased the expression of mucosal barrier markers, particularly occludin and zonula occludens-1. The 16S rRNA gene sequencing analysis demonstrated that treatment with celastrol altered the diversity and abundance of the gut microbiota. Spearman’s correlation analysis further revealed significant associations among gut microbial, renal injury markers, and serum lipid profiles. A subsequent renal transcriptome analysis revealed that celastrol significantly modulated the renal transcriptional landscape, primarily by regulating genes associated with the PPAR signaling pathway and lipid metabolism. Further investigations demonstrated that celastrol significantly downregulated adipose differentiation-related protein expression and attenuated DKD progression by activating the PPAR pathway. Conclusions: This study demonstrates that celastrol alleviates both colonic and renal injuries by modulating the gut-kidney axis through PPAR-mediated lipid metabolism regulation, indicating its potential as a therapeutic approach for DKD management.