Multi-omics analysis reveals the pathogenesis of db/db mice diabetic kidney disease and the treatment mechanisms of multi-bioactive compounds combination from Salvia miltiorrhiza

Diabetic kidney disease (DKD) is a common diabetic complication. Salvia miltiorrhiza has significant therapeutic effects on diabetes complications, although the mechanism remains unclear. Here, biochemical indicators and pathological changes were used to screen out the optimal Salvia miltiorrhiza multi-bioactive compounds combination. Metabolomics, transcriptomics and proteomics were used to explore the pathogenesis of DKD. RT-PCR and parallel reaction monitoring targeted quantitative proteome analysis were utilized to investigate treatment mechanisms of the optimal Salvia miltiorrhiza multi-bioactive compounds combination. The db/db mice showed biochemical abnormalities and renal lesions. The possible metabolic pathways were steroid hormone biosynthesis and sphingolipid metabolism. The 727 differential genes found in transcriptomics were associated with biochemical indicators via gene network to finally screen 11 differential genes, which were mainly key genes of TGF-β/Smad and PI3K/Akt/FoxO signaling pathways. Salvia miltiorrhiza multi-bioactive compounds combination could significantly regulate the Egr1, Pik3r3 and Col1a1 genes. 11 differentially expressed proteins involved in the two pathways were selected, of which 9 were significantly altered in db/db mice compared to db/m mice. Salvia miltiorrhiza multi-bioactive compounds combination could callback Q9DBM2, S4R1W1, Q91Y97, P47738, A8DUK4, and A2ARV4. In summary, Salvia miltiorrhiza multi-bioactive compounds combination may ameliorate kidney injury in diabetes through regulation of TGF-β/Smad and PI3K/Akt/FoxO signaling pathways.