Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ferroptosis is a novel type of programmed cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. Accumulative studies have indicated diabetic nephropathy (DN) as an inflammatory disorder, which involved immune modulation both in the occurrence and progression of the disease. In addition, DN is also considered as the major threatening complication of Diabetes mellitus (DM). However, other forms of programmed cell death, such as autophagy, apoptosis and necrosis, have been reported to be associated with DN, while there are no effective drugs to alleviate the damage of DN. In this study, we explored whether ferroptosis was involved in the progression of DN both in vivo and in vitro. We first established DN models using streptozotocin (STZ) and db/db mice. Results showed significant changes of ferroptosis associated markers, like increased expression levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and decreased expression levels of glutathione peroxidase 4 (GPX4) in DN mice. Also lipid peroxidation products and iron content were increased in DN mice. Next, in vitro, ferroptosis inducer erastin or RSL3 could induce renal tubular cell death, while iron and high ACSL4 levels sensitised ferroptosis. Finally, ACSL4 inhibitor rosiglitazone (Rosi) was used in the development of DN, which improved survival rate and kidney function, reduced lipid peroxidation product MDA and iron content. In summary, we first found ferroptosis was involved in DN and ferroptosis might be as a future direction in the treatment of DN.
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PMID:Ferroptosis involves in renal tubular cell death in diabetic nephropathy. 3297 29

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.
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PMID:Inhibition of ferroptosis by up-regulating Nrf2 delayed the progression of diabetic nephropathy. 3315 39


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