Zhou Lu, Xue Xian, Hou Qing, Dai Chunsun
Center for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Department of Clinical Genetics, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Kidney Dis (Basel). 2021 Aug 3;8(1):57-71. doi: 10.1159/000517723. eCollection 2022 Jan.
Ferroptosis, an iron-dependent form of regulated necrosis mediated by lipid peroxidation, predominantly polyunsaturated fatty acids, is involved in postischemic and toxic kidney injury. However, the role and mechanisms for tubular epithelial cell (TEC) ferroptosis in kidney fibrosis remain largely unknown.
The aim of the study was to decipher the role and mechanisms for TEC ferroptosis in kidney fibrosis.
Mouse models with unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI) were generated.
We found that TEC ferroptosis exhibited as reduced glutathione peroxidase 4 (GPX4) expression and increased 4-hydroxynonenal abundance was appeared in kidneys from chronic kidney disease (CKD) patients and mouse models with UUO or IRI. Inhibition of ferroptosis could largely mitigate kidney injury, interstitial fibrosis, and inflammatory cell accumulation in mice after UUO or IRI. Additionally, treatment of TECs with (1S,3R)-RSL-3, an inhibitor of GPX4, could enhance cell ferroptosis and recruit macrophages. Furthermore, inhibiting TEC ferroptosis reduced monocyte chemotactic protein 1 (MCP-1) secretion and macrophage chemotaxis.
This study uncovers that TEC ferroptosis may promote interstitial fibrosis and inflammation, and targeting ferroptosis may shine a light on protecting against kidney fibrosis in patients with CKDs.
铁死亡是一种由脂质过氧化介导的铁依赖性程序性坏死形式，主要涉及多不饱和脂肪酸，参与缺血后和中毒性肾损伤。然而，肾小管上皮细胞（TEC）铁死亡在肾纤维化中的作用和机制仍 largely 未知。
本研究旨在阐明 TEC 铁死亡在肾纤维化中的作用和机制。
构建单侧输尿管梗阻（UUO）或缺血/再灌注损伤（IRI）小鼠模型。
我们发现，在慢性肾脏病（CKD）患者以及 UUO 或 IRI 小鼠模型的肾脏中，TEC 铁死亡表现为谷胱甘肽过氧化物酶 4（GPX4）表达降低和 4-羟基壬烯醛丰度增加。抑制铁死亡可在很大程度上减轻 UUO 或 IRI 小鼠的肾损伤、间质纤维化和炎性细胞积聚。此外，用 GPX4 抑制剂（1S，3R）-RSL-3 处理 TEC 可增强细胞铁死亡并募集巨噬细胞。此外，抑制 TEC 铁死亡可减少单核细胞趋化蛋白 1（MCP-1）分泌和巨噬细胞趋化性。
本研究揭示 TEC 铁死亡可能促进间质纤维化和炎症，靶向铁死亡可能为保护 CKD 患者免受肾纤维化提供思路。
