Objectives: Diabetic nephropathy (DN) is one of the most common complications in patients with diabetes, and the discovery of novel targeted therapeutic approaches for DN treatment still faces severe challenges. In the current study, we aimed to discover a novel natural product for potential DN treatment and determine its molecular mechanisms.
Materials and methods: Methylthiazoltetrazolium (MTT) assay was employed to evaluate cell viability. Transmission electron microscopy, GFP-LC3 fluorescence fusion plasmid, and Annexin V/PI apoptosis assay were carried out to determine cellular autophagy and apoptosis. Moreover, quantitative proteomics and bioinformatics analysis, Western blotting, and RNA interference were performed to investigate potential molecular mechanisms.
Results: Hispidulin displayed protective capacity on the high-glucose-induced podocyte injury models by activating autophagy and inhibiting apoptosis. The mechanism for hispidulin-induced autophagy was associated to Pim1 inhibition and the regulation of Pim1-p21-mTOR signaling axis. Moreover, quantitative proteomics and bioinformatics analysis revealed that the hispidulin-regulated Pim1 inhibition was associated to RAB18, NRas, PARK7, and FIS1.
Conclusions: These results indicate that hispidulin induces autophagy and inhibits apoptosis induced by high glucose in murine podocytes. This study will illuminate future developments in DN-targeted therapy.
Keywords: Autophagy; Diabetic nephropathy; Hispidulin; Pim1; Podocyte.
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