Dihydroartemisinin ameliorates renal tubulointerstitial fibrosis in diabetic nephropathy via restoring mitochondrial function via HIF-1α/HO-1 pathway

Dihydroartemisinin (DHA) is a potential therapeutic strategy in multiple diseases, but its effects on Diabetic nephropathy (DN) have been not explored yet. Rats underwent unilateral ureteral obstruction surgery and injected by streptozotocin to induce DN, with treatment by DHA (15 and 30 mg/kg), and Losartan was used as a positive control. Blood glucose, and 24-h urine protein and glucose tolerance were detected to ensure kidney function. Periodic acid Schiff, hematoxylin and eosin and Masson staining were conducted to assess histological changes. Western blot and immunofluorescence were used for examining protein expression. HK-2 cells were subjected to high glucose (HG) exposure. Flow cytometry and Cell counting kit-8 were applied for assessing cell apoptosis and viability. Mitochondrial membrane potential (MMP), ATP production and respiratory chain complex activity were detected to assess mitochondrial function. DHA significantly improved renal functions of DN rats by reducing blood glucose and urine protein levels, inhibiting Kim-1 and NGAL expression and alleviated pathological damage dose-dependently. DHA relieved tubulointerstitial fibrosis through hindering epithelial-mesenchymal transition and ECM deposition, and attenuated mitochondrial dysfunction. In vitro experiments revealed that DHA ameliorated HG-caused ROS production, apoptosis and upregulation of HIF-1α/HO-1 in HK-2 cells. DHA might promote the degradation of HIF-1α via enhancing its ubiquitination, and HIF-1α/HO-1 was implicated with the suppressive effect of DHA on mitochondrial apoptosis in HG-exposed HK-2 cells. In conclusion, DHA exerts protective effects on renal tubulointerstitial fibrosis in DN.