Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

Abstract Diabetic kidney disease (DKD) is a major cause of end stage renal diseases worldwide. Despite successive interventions for delaying the progression of DKD, current treatments cannot reverse the pathological progression. Mefunidone (MFD) is a new compound with potent antifibrotic properties, but the effect of MFD on DKD remains unknown. Therefore, we investigated the protective effects of MFD in both models of the db/db type 2 diabetes (T2D) and streptozotocin (STZ)‐induced type 1 diabetes (T1D) models. Compared with the model group, MFD treatment significantly reduced pathological changes observed by PAS staining, PASM staining, and Masson staining in vivo. To further elucidate the potential mechanisms, we discovered MFD treatment notably restored podocyte function, alleviated inflammation, abated ROS generation, inhibited the TGF‐β1/SAMD2/3 pathway, suppressed the phosphorylation levels of MAPKs (ERK1/2, JNK, and P38), and reduced epithelial‐to‐mesenchymal transition(EMT). In conclusion, these findings demonstrate the effectiveness of MFD in diabetic nephropathy and elucidate its possible mechanism.