GSK3β调控Nrf2介导的铁死亡在AKI到CKD转变中的作用机制研究

Chronic kidney disease (CKD) is becoming a global public health problem. Epidemiological studies have shown that acute renal injury (AKI) is an independent and important risk factor for CKD, however, the pathophysiological mechanisms of AKI to CKD transition remains uncertain. Studies have shown that the oxidative damage of renal tubular epithelial cells was the key factor in the pathogenesis of maladaptive repair after AKI and progress to CKD, but also induced Ferroptosis and had effect on AKI. Besides, the vital regulatory factor for maintaining redox balance and Ferroptosis is Nuclear Factor-erythroid 2-related Factor 2 (Nrf2), and glycogen synthase kinase 3β (GSK3β) was considered to be the pivotal mechanism of Nrf2 regulation in delayed stage. Previous studies have found increased GSK3β, damaged oxidative stress and Ferroptosis in CKD samples, and inhibition of GSK3β increased Nrf2 nuclear expression and activity, promoted cellular incomplete repair，inhibited AKI to CKD transition. Therefore, we proposed a new hypothesis: GSK3β was involved in regulating Nrf2-mediated Ferroptosis in AKI to CKD transition. By using conditional GSK3β knockout and inhibitor treatment, this study would explore the mechanism of AKI to CKD transition in vivo and in vitro，may serve as a pragmatic therapeutic target for modifying the long-term sequelae of AKI.

慢性肾脏病（CKD）已成为威胁公众健康的全球问题。流行病学研究表明急性肾损伤（AKI）是CKD的独立和重要危险因素，但是AKI到CKD转变的发病机制尚不明确。研究发现氧化应激是造成AKI后肾小管修复受损以及进展为CKD的重要机制，且能诱导铁死亡的发生，影响AKI的预后。Nrf2是调节细胞氧化应激反应和铁死亡的关键因子，而GSK3β是细胞受刺激后延迟阶段对Nrf2调控的主要机制。前期研究发现CKD肾脏组织GSK3β表达增多，氧化应激损伤和铁死亡明显；抑制GSK3β能增强Nrf2的核表达和活性，促进细胞损伤修复，延缓AKI到CKD的进展。由此提出全新的假说：GSK3β通过调控Nrf2介导的铁死亡，影响细胞损伤修复再生，参与AKI到CKD的转变。本研究借助特异性GSK3β基因敲除小鼠和小分子抑制剂，结合体内、体外模型系统探讨AKI到CKD转变的作用机制，寻找改善AKI长期预后的有效治疗新靶点。

慢性肾脏病（CKD）已成为威胁全球公众健康的全球问题，流行病学研究表明，AKI是CKD进展的独立和重要危险因素，但是AKI到CKD转变的发表机制尚不明确。研究发现氧化应激是造成AKI后肾小管修复受损以及进展为CKD的重要机制，且能诱导铁死亡发生，影响AKI的预后，Nrf2是调节细胞氧化应激和铁死亡的关键因子，而GSK3β是细胞受刺激后延迟阶段对Nrf2调控的主要机制。前期研究发现CKD肾脏组织GSK3β表达增多，氧化应激损伤和铁死亡明显；抑制GSK3β能增强Nrf2的核表达和活性，促进细胞损伤修复，延缓AKI到CKD的进展。因此假设：GSK-3β通过调控Nrf2介导的铁死亡，影响细胞损伤修复再生，参与AKI到CKD的转变。本研究拟借助叶酸诱导的肾损伤模型和体外培养的肾小管上皮细胞，探索GSK-3β调控Nrf2介导的铁死亡在AKI到CKD转变中的作用及机制，为寻找改善AKI长期预后的有效治疗新靶点提供理论依据。研究发现：在CKD患者肾组织中，GPX4表达减少，铁死亡增多；在叶酸诱导小鼠肾损伤以及肾小管上皮细胞过氧化氢损伤模型中，特异性抑制GSK3β表达后，GPX4表达增加，铁死亡减轻，而这种保护作用也会被Nrf2抑制剂Trig消除。因此，研究结果表明，以GSK3β为治疗靶标能够增强Nrf2介导的抗氧化反应，减轻铁死亡，促进肾小管上皮细胞修复再生，这些发现为探索延缓AKI到CKD进展的靶向治疗提供理论依据。