Wogonoside ameliorates oxidative damage in tubular epithelial cells of diabetic nephropathy by modulating the HNF4A-NRF2 axis

Abstract

Diabetic nephropathy (DN), a leading cause of end-stage renal disease, presents significant challenges due to its complex pathophysiology and limited effective treatment options. Increasing evidence suggests that tubular injury is an early event preceding glomerular damage in DN. Wogonoside, a natural flavonoid derived from Scutellaria baicalensis, has not been previously reported for DN treatment. This study aims to investigate the protective effects and underlying mechanisms of wogonoside on renal tubular epithelial cells (TECs) in DN. The results showed that wogonoside mitigates high glucose (HG)-induced oxidative stress in TCMK-1 cells. Additionally, wogonoside protects renal function, reduces renal tubular damage, and modulates the oxidative stress response in HFD/STZ-induced DN mouse model. Importantly, our results indicated that hepatocyte nuclear factor 4 alpha (HNF4A) expression is downregulated in the kidneys of DN mice and HG-induced TCMK-1 cells. Wogonoside can bind to HNF4A, upregulate its expression, and promote nuclear translocation. Bioinformatic analysis suggested that NRF2 might be a downstream signaling of HNF4A. This was confirmed by Co-IP and experiments involving HNF4A overexpression and NRF2 knockdown, which demonstrated that wogonoside regulates the HNF4A-NRF2 axis to alleviate oxidative stress in TECs. Collectively, these findings identify wogonoside as a possible therapeutic agent for DN, highlighting HNF4A as a promising target for intervention.