Liu Pan, Zhang Zhengdong, Chen Qiu
Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
Department of Orthopedics, School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2024 Dec 25;53(6):708-714. doi: 10.3724/zdxbyxb-2024-0114.
Diabetic nephropathy is a common microvascular complication of diabetes mellitus and one of the main causes of death in patients with diabetes mellitus. Ferroptosis is a newly discovered iron-dependent regulated cell death, which may contribute to the pathogenesis and development of diabetic nephropathy. Adenosine monophosphate-activated protein kinase (AMPK)-mediated ferroptosis-related signaling pathways can slow down the progression of diabetic nephropathy, but excessive activation of AMPK signaling pathway may induce cells to undergo autophagic death. Activation of the signaling pathway mediated by nuclear factor-erythroid 2-related factor (Nrf) 2 and heme oxygenase (HO)-1 can inhibit ferroptosis of cells and alleviate diabetic nephropathy. However, the regulatory effect of HO-1 on ferroptosis is bidirectional, and activation of HIF-1α/HO-1 pathway may lead to intracellular iron overload and ultimately promote ferroptosis. Transforming growth factor (TGF)-β1 mediated signaling pathways can accelerate lipid peroxidation by down-regulating the levels of SLC7A11/GSH/GPX4. The ferroptosis-related signaling pathways mediated by exosome lncRNAs/circRNAs/miRNAs are also involved in the pathogenesis and development of diabetic nephropathy. In addition, signaling pathways mediated by stimulator of interferon gene (STING) and the novel ferroptosis promoter acyl-CoA synthetase long-chain family (ACSL) 1 can induce ferroptosis to promote the progression of diabetic nephropathy. In this review, we focus on the roles of ferroptosis in diabetic nephropathy through the signaling pathways mediated by AMPK, Nrf2/HO-1, TGF-β and exosomes, to elaborate the pathogenesis and development of diabetic nephropathy, and the potential therapeutic target for diabetic nephropathy.
糖尿病肾病是糖尿病常见的微血管并发症，也是糖尿病患者主要死亡原因之一。铁死亡是新发现的一种铁依赖性调节性细胞死亡，可能参与糖尿病肾病的发病机制和发展过程。腺苷单磷酸激活蛋白激酶（AMPK）介导的铁死亡相关信号通路可减缓糖尿病肾病的进展，但AMPK信号通路过度激活可能诱导细胞发生自噬性死亡。核因子红细胞2相关因子（Nrf）2和血红素加氧酶（HO）-1介导的信号通路激活可抑制细胞铁死亡并减轻糖尿病肾病。然而，HO-1对铁死亡的调节作用具有双向性，HIF-1α/HO-1通路激活可能导致细胞内铁过载并最终促进铁死亡。转化生长因子（TGF）-β1介导的信号通路可通过下调SLC7A11/谷胱甘肽（GSH）/谷胱甘肽过氧化物酶4（GPX4）水平加速脂质过氧化。外泌体长链非编码RNA（lncRNAs）/环状RNA（circRNAs）/微小RNA（miRNAs）介导的铁死亡相关信号通路也参与糖尿病肾病的发病机制和发展过程。此外，干扰素基因刺激因子（STING）和新型铁死亡促进因子酰基辅酶A合成酶长链家族（ACSL）1介导的信号通路可诱导铁死亡，促进糖尿病肾病进展。在本综述中，我们聚焦于通过AMPK、Nrf2/HO-1、TGF-β和外泌体介导的信号通路，阐述铁死亡在糖尿病肾病中的作用，以阐明糖尿病肾病的发病机制和发展过程，以及糖尿病肾病潜在的治疗靶点。
