AhR活化保护草酸钙结晶诱导的肾小管上皮细胞损伤的机制研究

Urolithiasis is one of the most common diseases of the urinary system. Many kidney stone patients suffered from renal tubular epithelial injury due to the long-term chronic inflammatory stimulation, leading to chronic nephropathy and even end-stage nephropathy. M1 macrophage polarization plays a key role in calcium oxalate nephrocalcinosis induced renal tubular epithelial cell injury. AhR is an important regulatory molecule in cell signaling pathways such as apoptosis, inflammation and immune response, and is involved in many pathophysiological processes. Studies have found that AhR activation could regulate the polarization of macrophages toward M2 phenotype and inhibit the inflammatory injury. Based on the preliminary experiments, we performed miRNA expression profiling using microarrays in macrophages with AhR overexpression, and identified that mir-142 was highly expressed. IRF1/IRF9 play an important role in pathogen-induced macrophage polarization and M1 macrophage mediated inflammatory injury. Further bioinformatics analysis predicted that IRF1/IRF9 were the directly targeted genes of mir-142. This study intends to explore the molecular mechanism of AhR activation promoting M2 macrophage polarization through the mir-142-IRF1/IRF9 pathway to protect calcium oxalate nephrocalcinosis induced renal tubular epithelial cell injury, so as to enrich the molecular biological mechanism of calcium oxalate nephrocalcinosis and provide new strategies and targets for its precise treatment.

泌尿系结石是泌尿系统最常见的疾病之一，很多肾结石患者因长期反复炎症刺激会引起肾小管上皮损伤，导致慢性肾病甚至终末期肾病。巨噬细胞向M1极化在草酸钙结晶诱导的肾小管上皮细胞损伤中起着非常关键的作用。AhR是细胞凋亡、炎症及免疫反应等细胞信号通路中的重要调节分子，参与许多病理生理过程。研究发现，AhR活化可以调节巨噬细胞向M2极化，抑制炎症反应。申请者前期研究中AhR过表达后的巨噬细胞行miRNA芯片表达谱分析，发现miR-142差异性高表达。IRF1/IRF9在参与病原体诱导巨噬细胞极化及M1介导的炎症损伤中具有重要作用，且生物信息学预测IRF1/IRF9是miR-142的直接靶基因。本研究拟探讨AhR活化通过miR-142-IRF1/IRF9通路促进M2巨噬细胞极化保护草酸钙结晶诱导肾小管上皮细胞损伤的分子机制，从而丰富草酸钙结石肾病发病分子生物学机制，为其精准化治疗提供新的策略和靶点。

泌尿系结石是泌尿系统最常见的疾病之一，其具有发病率高和复发率高的特点。很多肾结石患者因长期反复炎症刺激会引起肾小管上皮损伤，导致慢性肾病甚至终末期肾病，给患者造成了较大的健康损害和经济负担，因此研究其发病机制和寻找潜在的防治靶点具有了重要意义。.巨噬细胞在慢性炎症损伤中扮演着重要的角色，其向M1极化在草酸钙结晶诱导的肾小管上皮细胞损伤中起着非常关键的作用，调控巨噬细胞的极化方向成为了结石防治的潜在有效靶点。AhR是细胞凋亡、炎症及免疫反应等细胞信号通路中的重要调节分子，参与许多病理生理过程。研究发现，AhR活化可以调节巨噬细胞向M2极化，抑制炎症反应。通过前期试验结果，本研究发现AhR活化后通过与miR-142a启动子结合并转录激活miR-142a，进而靶向抑制IRF1和HIF-3α表达，减少M1巨噬细胞极化，促进M2巨噬细胞极化，从而调控巨噬细胞引发的慢性炎症反应，减轻草酸钙结晶诱导的肾小管上皮细胞损害。.本研究揭示了AhR保护草酸钙结晶诱导肾小管上皮细胞损伤的分子机制，丰富了草酸钙结石肾病发病分子生物学机制，为其精准化治疗提供新的策略和靶点，具有较好的临床应用前景。