Icariin alleviates diabetic renal interstitial fibrosis aggravation by inhibiting miR-320a-3p targeting BMP6.

Diabetic nephropathy is a common complication of diabetes, accumulating evidence underscores the pivotal role of tubulointerstitial fibrosis in the progression of diabetic nephropathy. However, the underlying mechanisms remain incompletely understood. Although the mechanisms in diabetic nephropathy fibrosis have been the focus of many studies, only limited information is currently available concerning microRNA regulation in tubulointerstitial fibrosis. In this study, we aimed to investigate the roles of miR-320a-3p and bone morphogenetic protein-6 (BMP6) in tubulointerstitial fibrosis. After inducing fibrosis with high glucose in HK-2 cells, we found that miR-320a-3p is significantly up-regulated, whereas BMP6 is markedly down-regulated. These changes suggest close link between miR-320a-3p and BMP6 in tubulointerstitial fibrosis. To elucidate this phenomenon, miR-320a-3p mimic, inhibitor and siBMP6 were employed. We observed in miR-320a-3p mimic group the fibrosis marker include alpha smooth muscle actin and type I collagen was significantly up-regulated, whereas BMP6 exhibited the opposite trend. Additionally, we found icariin could alleviate tubulointerstitial fibrosis by downregulation the miR-320a-3p expression. In conclusion, miR-320a-3p promotes tubulointerstitial fibrosis during the development of DN by suppressing BMP signal pathway activity via inhibiting BMP6 expression. Suggesting that miR-320a-3p represents a potential therapeutic target for tubulointerstitial fibrosis induced by diabetic nephropathy.

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

BACKGROUND: 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. PURPOSE: This study aimed to investigate the ameliorative mechanism of ICA in diabetes mellitus rats and MPC-5 cells. METHODS: 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. RESULTS: 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. CONCLUSION: 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.