Morroniside attenuates podocytes lipid deposition in diabetic nephropathy: A network pharmacology, molecular docking and experimental validation study.

Background: Dysregulation of lipid metabolism is a key factor influencing the progression of diabetic nephropathy (DN). Morroniside (MOR) is a major active compound isolated from the traditional Chinese herb Cornus officinalis, our previous research found that it can improve the lipid deposition of renal tubular epithelial cells. The purpose of this study is to explore whether MOR can improve podocyte lipid deposition and its mechanism of reducing DN.

Methods: Initially, we used network pharmacology and bioinformatics techniques to predict the relationship between renal lipid metabolism of MOR and DN. Subsequently, the binding activity of MOR with lipid-related proteins was studied by molecular docking to determine how MOR acts through these proteins. After determining the target of MOR, animal experiments and cell tests were carried out to verify it.

Results: Using network pharmacology, bioinformatics, and molecular docking, target proteins for MOR treatment of DN were predicted and screened, including PGC-1α, LXRs, ABCA1, PPARY, CD36, and nephrin. It is particularly noted that MOR effectively binds to PGC-1α, while LXRs, ABCA1, PPARY and CD36 are downstream molecules of PGC-1α. Silencing the PGC-1α gene significantly reduced the therapeutic effects of MOR. Conversely, in groups without PGC-1α knockdown, MOR was able to increase the expression levels of PGC-1α and influence the expression of downstream proteins. Furthermore, through in vivo and in vitro experiments, utilizing techniques such as lipid droplet staining, PAS, MASSON staining, immunofluorescence, and Western blot, we found that MOR effectively elevated the expression levels of the podocyte protein nephrin and lipid metabolism-regulating proteins PGC-1α, PPARY, and ABCA1, while significantly inhibiting the expression of the lipid accumulation promoter CD36.

Conclusion: MOR can regulate the cholesterol efflux in podocytes via the PGC-1α/LXRs/ABCA1 signaling pathway, and control cholesterol intake via the PGC-1α/PPARY/CD36 signaling pathway, thereby ameliorating lipid deposition in DN.