Department of Pediatric Critical Care Medicine, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiaotong University, Shanghai, China.
Department of Pediatric Respiratory Department, Xinhua Hospital, Affiliated to the Medical School of Shanghai Jiaotong University, Shanghai, China.
Physiol Genomics. 2023 Nov 1;55(11):504-516. doi: 10.1152/physiolgenomics.00023.2023. Epub 2023 Aug 29.
Previously, we found that the incidence of kidney injury in patients with chronic hypoxia was related to the partial pressure of arterial oxygen. However, at oxygen concentrations that contribute to kidney injury, the changes in the relationship between microRNAs (miRNAs) and the hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) axis and the key miRNAs involved in this process have not been elucidated. Therefore, we elucidated the relationship between VEGF and kidney injury at different oxygen concentrations and the mechanisms mediated by miRNAs. Sprague-Dawley rats were exposed to normobaric hypoxia and categorized into six groups based on the concentration of the oxygen inhaled and injection of the angiogenesis inhibitor bevacizumab, a humanized anti-VEGF monoclonal antibody. Renal tissue samples were processed to determine pathological and morphological changes and HIF-1α, VEGF, and miRNA expression. We performed a clustering analysis of high-risk pathways and key hub genes. The results were validated using two Gene Expression Omnibus datasets (GSE94717 and GSE30718). As inhaled oxygen concentration decreased, destructive changes in the kidney tissues became more severe. Although the kidney possesses a self-protective mechanism under an intermediate degree of hypoxia (10% O), bevacizumab injections disrupted this mechanism, and VEGF expression was associated with the ability of the kidney to repair itself. rno-miR-124-3p was identified as a crucial miRNA; a key gene target, , was identified during this process. VEGF plays an important role in kidney protection from injury under different hypoxia levels. Specific miRNAs and their target genes may serve as biomarkers that provide new insights into kidney injury treatment. Renal tolerance to hypoxic environments is limited, and the degree of hypoxia does not show a linear relationship with angiogenesis. VEGF plays an important role in the kidney's self-protective mechanism under different levels of hypoxia. miR-124-3p may be particularly important in kidney repair, and it may modulate VEGF expression through the miR-124-3p/Mapk14 signaling pathway. These microRNAs may serve as biomarkers that provide new insights into kidney injury treatment.
先前，我们发现慢性缺氧患者的肾损伤发生率与动脉血氧分压有关。然而，在导致肾损伤的氧浓度下，miRNAs（miRNA）与缺氧诱导因子-1α（HIF-1α）-血管内皮生长因子（VEGF）轴之间的关系变化以及该过程中涉及的关键 miRNA 尚未阐明。因此，我们阐明了不同氧浓度下 VEGF 与肾损伤的关系以及 miRNA 介导的机制。将 Sprague-Dawley 大鼠暴露于常压低氧环境中，并根据吸入氧浓度和血管生成抑制剂贝伐单抗（一种人源化抗 VEGF 单克隆抗体）的注射情况将其分为六组。处理肾组织样本以确定病理和形态变化以及 HIF-1α、VEGF 和 miRNA 表达。我们对高风险途径和关键枢纽基因进行聚类分析。使用两个基因表达综合数据集（GSE94717 和 GSE30718）验证了结果。随着吸入氧浓度的降低，肾脏组织的破坏性变化变得更加严重。尽管在中度缺氧（10% O）下肾脏具有自我保护机制，但贝伐单抗注射破坏了这种机制，并且 VEGF 表达与肾脏自我修复的能力相关。rno-miR-124-3p 被鉴定为关键 miRNA；在此过程中，确定了一个关键基因靶标， 。VEGF 在不同缺氧水平下对肾脏损伤的保护作用很重要。特定的 miRNA 及其靶基因可能作为生物标志物，为肾脏损伤治疗提供新的见解。肾脏对低氧环境的耐受能力是有限的，缺氧程度与血管生成之间没有线性关系。VEGF 在不同水平的缺氧下对肾脏的自我保护机制起着重要作用。miR-124-3p 在肾脏修复中可能特别重要，并且可能通过 miR-124-3p/Mapk14 信号通路调节 VEGF 表达。这些 miRNA 可能作为生物标志物，为肾脏损伤治疗提供新的见解。
