Icariin protects podocytes from NLRP3 activation by Sesn2-induced mitophagy through the Keap1-Nrf2/HO-1 axis in diabetic nephropathy

Icariin (ICA) is a flavonoid extract obtained from Herba epimedii that has been proven to exert multiple pharmacological activities, including antifibrotic and anti-inflammatory activities.This study aimed to investigate the ameliorative mechanism of ICA in diabetes mellitus rats and MPC-5 cells.We administered ICA at 3 different dosages (20 mg/kg, 40 mg/kg, 80 mg/kg) to streptozotocin (STZ)-treated rats and (1 μM, 3 μM, 10 μM) to high glucose (HG)-treated MPC-5 cells. We also chose irbesartan (IRB) (13.5 mg/kg in rats, 1 μM in cells) as a positive control drug to evaluate the ICA pharmacological effect. After administration, the kidneys of rats and MPC-5 cells were harvested for experiments.After 8 weeks of oral administration, we found that the physiological index was improved by ICA and IRB. The results of immunohistochemistry, Western blot, and laser confocal imaging showed that mitophagy might play a key role in ICA-induced improvement. In further research, we found that ICA could activate Nrf2, suppress NLRP3 and degrade Keap1 via Sesn2-dependant mitophagy. To verify our hypothesis, we blocked the mitophagy signalling pathway via Sesn2 siRNA. The results showed that ICA-induced NLRP3 suppression and mitophagy vanished.In summary, we conclude that ICA can increase Sesn2-induced mitophagy to inhibit NLRP3 inflammasome activation by the Keap1-Nrf2/HO-1 axis in diabetic nephropathy rats. This might be the underlying mechanism of ICA's protective effect in diabetic nephropathy.