APC ameliorates idiopathic membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis.
APC ameliorates idiopathic membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis.
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APC 通过 ERK1/2/YB-1/PLA2R1 轴影响足细胞凋亡，改善特发性膜性肾病
DOI：
10.1007/s11010-022-04650-7
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发表时间：
2023-09
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
特发性膜性肾病（IMN）是成人肾病综合征的一个重要致病类别。PLA2R1暴露对于触发PLA2R1相关IMN的发病机制至关重要。然而，IMN的发病机制和治疗的分子机制仍有待进一步阐明。采用qPCR定量检测IMN患者活化蛋白C （activated protein C， APC）和PLA2R1的表达变化。建立了酶酶酶激活血清（ZAS）诱导的IMN足细胞体外模型。通过流式细胞术和caspase‑3检测足细胞凋亡。western blotting检测APC、p-ERK1/2、ERK1/2、YB-1和PLA2R1的表达水平。采用双荧光报告系统检测YB-1与PLA2R1的调控关系。在IMN患者中，PLA2R1表达水平升高，APC表达水平降低。体外足细胞中添加APC后，ERK1/2磷酸化水平升高，可促进YB-1易位至细胞核，从而在细胞转录水平上降低PLA2R1的表达，从而抑制足细胞凋亡。我们的研究首次报道了APC通过ERK1/2/YB-1/PLA2R1轴影响足细胞凋亡，从而改善膜性肾病。本研究将为PLA2R1高表达的IMN患者提供新的靶向治疗方法。
Idiopathic membranous nephropathy (IMN) belongs to an important pathogenic category of adult nephrotic syndrome. PLA2R1 exposure is critical for triggering the pathogenesis of PLA2R1-related IMN. However, the pathogenesis of IMN and the molecular mechanism of treatment remain to be further clarified. The expression changes of activated protein C (APC) and PLA2R1 in IMN patients were quantified by qPCR. A zymosan activated serum (ZAS)-induced IMN podocyte model was established in vitro. Podocyte apoptosis was detected via flow cytometry and caspase‑3 assay. The expression levels of APC, p-ERK1/2, ERK1/2, YB-1 and PLA2R1 were detected by western blotting. The regulation relationship between YB-1 and PLA2R1 was detected by dual fluorescent reporter system. In IMN patients, the expression level of PLA2R1 was increased, whereas the expression level of APC was decreased. When APC was added to podocytes in vitro, the phosphorylation of ERK1/2 was increased, which could promote the translocation of YB-1 to the nucleus that reduces the expression of PLA2R1 at the cellular transcriptional level, thereby inhibiting podocyte apoptosis. Our study is the first to report that APC can improve membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis. This study will provide a new targeted therapy for IMN patients with high PLA2R1 expression.
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