Interstitial HIF1A induces an estimated glomerular filtration rate decline through potentiating renal fibrosis in diabetic nephropathy
Interstitial HIF1A induces an estimated glomerular filtration rate decline through potentiating renal fibrosis in diabetic nephropathy
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DOI：
10.1016/j.lfs.2019.117109
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发表时间：
2020-01-15
期刊：
影响因子：
6.1
通讯作者：
Hao, Chuanming
中科院分区：
文献类型：
--
作者：
Li, Xiyue;Yang, Sisi;Hao, Chuanming
目的：本研究旨在确定与糖尿病肾病（DN）患者肾小球滤过率（eGFR）恶化有关的间质分子。材料和方法：采用加权基因共表达网络分析（Weighted gene co-expression network analysis， WGCNA）将DN的小管间质基因表达谱与eGFR值联系起来。利用线性回归模型分析了eGFR与网络中各子域调节器的关系。基因集富集分析（GSEA）用于检测主要与必需调节因子相关的分子变化。主要发现：发现四个共表达模块与eGFR值密切相关。来自这些模块的基因在纤维化相关的生物过程（细胞外基质（ECM）组织和细胞粘附）和途径（整合素信号传导和ECM受体相互作用）中被过度代表。在基因相互作用网络的子结构域中，缺氧诱导因子1A （HIF1A）的表达与eGFR呈最负相关（R-2 = 0.417, P = 0.026）。发现HIF1A与其靶基因正相关，表明HIF1A的转录活性增强。我们还发现HIF1A与CCAAT增强子结合蛋白δ (CEBPD)呈正相关（r = 0.731, P = 0.011），后者是HIF1A转录的激活因子。此外，GSEA显示HIF1A高表达的样本富含纤维化相关信号，如ecm受体相互作用和细胞粘附。有趣的是，血管上皮生长因子A （VEGFA）表达降低，而HIF1A表达升高（R-2 = 0.733, P = 0.001），表明VEGFA的缺失可能加剧缺氧，刺激HIF1A诱导。意义：本研究提示间质HIF1A可能参与DN肾间质纤维化。
Aims: This study aimed to identify interstitial molecules that were responsible for the deterioration of the esiantimated glomerular filtration rate (eGFR) in diabetic nephropathy (DN).Materials and methods: Weighted gene co-expression network analysis (WGCNA) was used to link the tubulointerstitial gene expression profile of DN to eGFR values. The relationship of eGFR with each sub-domain regulator in the network was analyzed with the linear regression model. Gene sets enrichment analysis (GSEA) was applied to detect the molecular changes mostly relating to the essential regulators.Key findings: Four co-expression modules were found strongly correlating with eGFR values. Genes from these modules were over-represented in fibrosis-related biological processes (extracellular matrix (ECM) organization and cell adhesion) and pathways (integrin signaling and ECM-receptor interaction). Of sub-domains in the gene interaction network, the expression of hypoxia-inducible factor 1A (HIF1A) was most negatively correlated with eGFR (R-2 = 0.417, P = 0.026). The positive correlations between HIF1A and its target genes were found, indicating an enhanced transcriptional activity of HIF1A. We also found that HIF1A positively correlated with CCAAT enhancer binding protein delta (CEBPD) (r = 0.731, P = 0.011), an activator of HIF1A transcription. Moreover, GSEA showed that samples with high HIF1A expression were enriched with fibrosis associated signaling, like ECM-receptor interaction and cell adhesion. Intriguingly, vascular epithelial growth factor A (VEGFA) expression decreased while HIF1A increased (R-2 = 0.733, P = 0.001), suggesting VEGFA loss may exacerbate hypoxia and stimulate HIF1A induction.Significance: The present study suggested that interstitial HIF1A may be involved in renal interstitial fibrosis in DN.