Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain; REDINREN, Madrid, Spain.
Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Cordoba, Spain.
Nefrologia (Engl Ed). 2020 Jul-Aug;40(4):384-394. doi: 10.1016/j.nefro.2020.03.005. Epub 2020 Jul 2.
Cell death is a finely regulated process occurring through different pathways. Regulated cell death, either through apoptosis or regulated necrosis offers the possibility of therapeutic intervention. Necroptosis and ferroptosis are among the best studied forms of regulated necrosis in the context of kidney disease. We now review the current evidence supporting a role for ferroptosis in kidney disease and the implications of this knowledge for the design of novel therapeutic strategies. Ferroptosis is defined functionally, as a cell modality characterized by peroxidation of certain lipids, constitutively suppressed by GPX4 and inhibited by iron chelators and lipophilic antioxidants. There is functional evidence of the involvement of ferroptosis in diverse forms of kidneys disease. In a well characterized nephrotoxic acute kidney injury model, ferroptosis caused an initial wave of death, triggering an inflammatory response that in turn promoted necroptotic cell death that perpetuated kidney dysfunction. This suggests that ferroptosis inhibitors may be explored as prophylactic agents in clinical nephrotoxicity or ischemia-reperfusion injury such as during kidney transplantation. Transplantation offers the unique opportunity of using anti-ferroptosis agent ex vivo, thus avoiding bioavailability and in vivo pharmacokinetics and pharmacodynamics issues.
细胞死亡是通过不同途径发生的精细调节过程。通过细胞凋亡或调节性细胞坏死的调节性细胞死亡为治疗干预提供了可能性。细胞坏死和铁死亡是在肾脏疾病背景下研究得最好的调节性细胞坏死形式之一。我们现在回顾支持铁死亡在肾脏疾病中的作用的现有证据，以及这一知识对设计新的治疗策略的影响。铁死亡在功能上被定义为一种细胞模式，其特征是某些脂质的过氧化，被 GPX4 持续抑制，并被铁螯合剂和亲脂性抗氧化剂抑制。有功能证据表明铁死亡参与了多种形式的肾脏疾病。在一种特征明确的肾毒性急性肾损伤模型中，铁死亡导致了最初的死亡波，引发了炎症反应，进而促进了促进肾功能障碍的坏死性细胞死亡。这表明铁死亡抑制剂可能作为预防剂在临床肾毒性或缺血再灌注损伤中（如在肾移植期间）进行探索。移植提供了使用抗铁死亡剂的独特机会，从而避免了生物利用度以及体内药代动力学和药效动力学问题。
