Umbelliferone delays the progression of diabetic nephropathy by inhibiting ferroptosis through activation of the Nrf-2/HO-1 pathway

Ferroptosis is a novel form of lipid reactive oxygen species and iron dependent cell death, and it has been shown to be involved in renal tubular injury in diabetic mice. Nrf2 plays an important role in regulating lipid peroxidation and is closely related to ferroptosis. Umbelliferone has antioxidant, anti-glycation and protective effects on diabetic mice. However, the potential mechanisms and underlying effects of these effects in diabetic nephropathy (DN) remain to be investigated.10-week-old male C57BLKS/J db/db, C57BLKS/J db/m mice and HK-2 cells cultured with high glucose were used as experimental objects in this study. ROS levels, GSH, MDA and iron content were detected.We found that Umbelliferone can significantly improve the renal pathological damage and ROS accumulation of db/db mice, and inhibit ferroptosis, such as the down-regulation of ACSL4 and the up-regulation of GPX4. Meanwhile, Nrf2 and HO-1 expression were up-regulated. We demonstrated that knockdown of Nrf2 blocked the inhibitory effect of Umbelliferone on ferroptosis in renal tubule cells induced by high glucose.These results suggest that Umbelliferone has a protective effect on DN, possibly by activating the Nrf2/HO-1 pathway, thus attenuating the level of high glucose-induced ferroptosis.