VEGFA promotes the occurrence of PLA2R-associated idiopathic membranous nephropathy by angiogenesis via the PI3K/AKT signalling pathway.
VEGFA promotes the occurrence of PLA2R-associated idiopathic membranous nephropathy by angiogenesis via the PI3K/AKT signalling pathway.
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VEGFA通过PI3K/AKT信号通路促进血管生成促进PLA2R相关特发性膜性肾病的发生
DOI：
10.1186/s12882-022-02936-y
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发表时间：
2022-09-16
期刊：
影响因子：
2.3
通讯作者：
中科院分区：
文献类型：
--
作者：
M型磷脂酶A2受体（PLA 2 R）相关的特发性膜性肾病（IMN）是一种常见的成人免疫相关疾病。血管内皮生长因子A（VEGFA）是血管生成的关键介质，导致许多肾脏疾病。然而，VEGFA在IMN中的作用知之甚少。在本研究中，我们从Gene Expression Omnibus（GEO）下载了微阵列数据GSE 115857。用R软件对差异表达基因进行鉴定。cytoHubba插件用于从蛋白质-蛋白质相互作用网络中识别枢纽基因。基因集富集分析（GSEA）用于鉴定IMN中的信号通路。CCK-8测定人血管内皮细胞（HVECs）的细胞活力。然后，被动Heymann肾炎（PHN）诱导大鼠通过一个单一的尾静脉注射抗Fx 1A抗血清。用VEGFA抑制剂贝伐单抗（BV）处理的动物，用盐水作为阳性对照。蛋白尿通过生化指标进行评估。免疫组织化学和免疫荧光法检测相关蛋白表达。电镜观察肾小球基底膜（GBM）厚度。我们发现了3个hub基因，包括一个上调基因VEGFA和两个下调基因JUN和FOS，它们与PLA 2 R相关IMN的发生密切相关。途径富集分析发现，VEGFA诱导的生物学过程与PI 3 K/Akt信号通路相关。GSEA表明GSE 115857中DEGs的信号通路集中于血管生成，其中VEGFA作为核心基因。我们用免疫组化证实了IMN肾活检标本中VEGFA、PI 3 K和AKT的高表达。在HVEC中，我们发现BV以时间和剂量依赖性方式抑制细胞活力。在体内，我们发现低剂量的BV通过抑制VEGFA/PI 3 K/AKT信号转导来减轻蛋白尿。同时，小剂量BV可减轻GBM的增厚。VEGFA/PI 3 K/AKT信号通路可能在IMN的发病机制中发挥重要作用，为IMN的治疗提供新的靶点。在线版本包含补充材料，可通过10.1186/s12882-022-02936-y获得。
The M-type phospholipase A2 receptor (PLA2R)-associated idiopathic membranous nephropathy (IMN) is a common immune-related disease in adults. Vascular endothelial growth factor A (VEGFA) is the key mediator of angiogenesis, which leads to numerous kidney diseases. However, the role of VEGFA in IMN is poorly understood. In the present study, we downloaded the microarray data GSE115857 from Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) were identified with R software. The cytoHubba plug-in were used to identify hub genes from the protein–protein interaction network. Gene set enrichment analysis (GSEA) was used to identify signalling pathway in IMN. CCK8 was performed to assess the cell viability in human vascular endothelial cells (HVECs). Then, passive Heymann nephritis (PHN) was induced in rats by a single tail vein injection of anti-Fx1A antiserum. Animals treated with VEGFA inhibitor bevacizumab (BV), with saline as a positive control. Proteinuria was evaluated by biochemical measurements. Immunohistochemistry and immunofluorescence was used to evaluate relative proteins expression. Electron microscopy was performed to observe the thickness of the glomerular basement membrane (GBM). We revealed 3 hub genes, including one up-regulated gene VEGFA and two down-regulated genes JUN and FOS, which are closely related to the development of PLA2R-associated IMN. Pathway enrichment analysis found that the biological process induced by VEGFA is associated with PI3K/Akt signalling. GSEA showed that the signalling pathway of DEGs in GSE115857 was focused on angiogenesis, in which VEGFA acts as a core gene. We confirmed the high expression of VEGFA, PI3K, and AKT in IMN renal biopsy samples with immunohistochemistry. In HVECs, we found that BV suppresses cell viability in a time and dose dependent manner. In vivo, we found low dose of BV attenuates proteinuria via inhibiting VEGFA/PI3K/AKT signalling. Meanwhile, low dose of BV alleviates the thickening of the GBM. VEGFA/PI3K/AKT signalling may play significant roles in the pathogenesis of IMN, which may provide new targets for the treatment of IMN. The online version contains supplementary material available at 10.1186/s12882-022-02936-y.
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