Inhibition of ferroptosis by up-regulating Nrf2 delayed the progression of diabetic nephropathy

• Published in: Free radical biology & medicine 2021-01, Vol.162, p.435-449
• Main Authors: Li, Shuangwen, Zheng, Lisi, Zhang, Jun, Liu, Xuejun, Wu, Zhongming
• Format: Article
• Language: English
• Subjects: Animals; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - genetics; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - genetics; Diabetic nephropathy; Fenofibrate; Ferroptosis; Iron overload; Mice; Mice, Inbred DBA; NF-E2-Related Factor 2 - genetics; NFE2-Related factor 2; Reactive oxygen species
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2020.10.323

Diabetic nephropathy (DN) is now considered the leading cause of end-stage renal disease. In diabetes, the accumulation of reactive oxygen species (ROS) and iron overload are important determinants that promote the occurrence of DN. However, the underlying mechanism of how they cause diabetic kidney damage remains unclear. Ferroptosis, characterized by iron-dependent lipid peroxidation, provided us with a new idea to explore the progression of DN. Iron overload, reduced antioxidant capability, massive ROS and lipid peroxidation were detected in the kidneys of streptozotocin-induced DBA/2J diabetic mice and high-glucose cultured human renal proximal tubular (HK-2) cells, which were the symbolic changes of ferroptosis. Furthermore, the characteristic mitochondrial morphological changes of ferroptosis were observed in high glucose cultured cells. Additional treatment of Ferrostatin-1 (Fer-1) in DN models significantly rescued these changes and alleviated the renal pathological injuries in diabetic mice. Besides, the decreased NFE2-related factor 2 (Nrf2) was observed in DN models. The specific knockdown of Nrf2 increased the sensitivity of cells to ferroptosis in the high glucose condition. In Nrf2 knockdown cells, up-regulating Nrf2 by treating with fenofibrate improved the situation of ferroptosis, which was verified in RSL-3 induced cells. Moreover, the ferroptosis-related changes were inhibited by increasing Nrf2 in fenofibrate treated diabetic mice, which delayed the progression of DN. Collectively, we demonstrated that ferroptosis was involved in the development of DN, and up-regulating Nrf2 by treating with fenofibrate inhibited diabetes-related ferroptosis, delaying the progression of DN. Our research revealed the development mechanism of DN from a new perspective, and provide a new approach delaying the progression of DN. In diabetes, hyperglycemia causes the overload of redox-active (ferrous) iron and the accumulation of multiple sources of ROS, which provides conditions for the occurrence of ferroptosis. Simultaneously, the decreased glutathione (GSH) and glutathione peroxidase 4 (GPX4) weakened the resistance to oxidative stress, promoted the occurrence of lipid peroxidation, and ultimately led to cell ferroptosis. However, up-regulating Nrf2 by treating with fenofibrate could regulate the expression of GPX4, solute carrier family 7 member (SLC7A11), ferritin heavy chain 1 (FTH-1) and transferrin receptor 1 (TFR-1), which restored the antioxidant