Objective: To investigate whether dihydroartemisinin (DHA) attenuates ischaemia-reperfusion injury (IRI)-induced acute kidney injury (AKI) in mice by inhibiting oxidative stress and inflammation and to explore its potential molecular mechanisms.
Materials and methods: Network pharmacology analysis was used to screen relevant targets, and molecular docking of DHA with core targets was performed. Molecular dynamics simulation of the target with the lowest binding free energy, NQO1-DHA.The renal protective effect of DHA on the IRI-induced AKI mouse model was evaluated. The expression levels of NQO1, Nrf2 and other proteins were detected by Western blotting. The expression levels of Nrf2 and others were detected by immunohistochemistry (IHC) and immunofluorescence (IF).
Results: Through network pharmacological analysis, we obtained that PI3K/AKT and MAPK signaling pathway may be related to DHA in the treatment of AKI.Molecular dynamics simulation indicated that NQO1 is an important target protein for DHA to exert nephroprotective effects.Moreover, the potential molecular mechanisms were verified by experiments.DHA reduced the serum creatinine (Scr) and urea nitrogen (BUN) levels in AKI mice, significantly improved AKI pathology, alleviated oxidative stress and inflammatory injury, which may be related to its activation of the Nrf2 pathway and regulation of macrophage polarization.
Conclusions: Through network pharmacology, molecular dynamics simulation and experimental validation, we initially investigated that DHA alleviate AKI by ameliorating oxidative stress and inflammatory damage, which may be related to its activation of the Nrf2 pathway and the regulation of macrophage polarisation, which lays the foundation for subsequent in-depth study of the specific mechanism of action.
Keywords: Acute kidney injury; Dihydroartemisinin; Experimental validation; Ischaemia-reperfusiona; Molecular dynamics simulation; Network pharmacology.
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