Berberine inhibits ISG15 and pyroptosis to attenuate diabetic kidney disease inflammation and fibrosis

Diabetic kidney disease (DKD) is a microvascular complication of diabetes accompanied by inflammation and tubular fibrosis. Berberine (BBR), a plant alkaloid and traditional Chinese medicine, has been shown to have beneficial effects on DKD. However, its mechanism underlying its therapeutic effects in DKD remain to be fully elucidated. Herein, we investigated the protective effects of BBR on STZ/HFD-induced DKD mice and high glucose (HG)-treated renal tubular epithelial cells (TECs). Results showed that BBR reduced inflammation and tubular fibrosis in DKD mice. Meanwhile, BBR also reversed HG-induced inflammation and fibrosis in TECs. Mechanistically, qPCR and western blotting assays revealed that BBR abolished the HG-induced upregulation of ISG15 and the changes in the expression of pyroptosis-related proteins. Furthermore, overexpression of ISG15 in kidney and TECs significantly exacerbated renal tubular cell injury and abolished the protective effect of BBR against DKD. In conclusion, these results demonstrated that BBR can attenuate inflammation and tubular fibrosis in DKD by inhibiting ISG15 and pyroptosis, providing a new potential strategy for the treatment of DKD and highlighting the therapeutic potential of BBR in mitigating renal injury and fibrosis.