Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, 330006, Jiangxi Province, People's Republic of China.
Department of Cardiovascular Medicine, The Second Affiliated Hospital to Nanchang University, Nanchang, 330006, Jiangxi Province, People's Republic of China.
Mol Cell Biochem. 2023 Sep;478(9):1999-2011. doi: 10.1007/s11010-022-04650-7. Epub 2023 Jan 2.
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.
特发性膜性肾病（IMN）属于成人肾病综合征的重要致病类别之一。PLA2R1 的暴露对于触发 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。通过 qPCR 定量检测 IMN 患者中活化蛋白 C（APC）和 PLA2R1 的表达变化。体外建立了酵母聚糖激活血清（ZAS）诱导的 IMN 足细胞模型。通过流式细胞术和 caspase-3 测定检测足细胞凋亡。通过 Western blot 检测 APC、p-ERK1/2、ERK1/2、YB-1 和 PLA2R1 的表达水平。通过双荧光报告系统检测 YB-1 和 PLA2R1 之间的调节关系。在 IMN 患者中，PLA2R1 的表达水平增加，而 APC 的表达水平降低。当 APC 被添加到体外足细胞中时，ERK1/2 的磷酸化增加，这可以促进 YB-1 向核内易位，从而降低细胞转录水平上 PLA2R1 的表达，从而抑制足细胞凋亡。本研究首次报道 APC 可以通过影响足细胞凋亡来改善膜性肾病，通过 ERK1/2/YB-1/PLA2R1 轴。该研究将为 PLA2R1 表达水平高的 IMN 患者提供新的靶向治疗方法。
