高尿酸血症可引发肾脏炎细胞浸润及肾损伤,而肾脏疾病又能导致血清尿酸升高,形成恶性循环,但机制不清。我们前期证实:①高尿酸促进血管内皮细胞线粒体释放ROS,进而激活炎症小体;②高尿酸诱导肾小球内皮细胞LncRNA-HOTAIR的表达上调而吸附miR-22,进而促进其直接靶基因炎症小体NLRP3的表达。因此推测:高尿酸可通过HOTAIR增加NLRP3的表达和通过ROS激活NLRP3的双重途径,引起肾脏血管内皮细胞炎症反应和肾脏的炎症损伤。本工作将:验证HOTAIR可吸附miR-22继而促进NLRP3表达;明确高尿酸诱导产生的ROS通过解离TXNIP/TRX而活化NLRP3的机制;在HOTAIR-/-和TXNIP-/-小鼠验证上述机制。本工作将为尿酸性肾病的临床诊治提供全新的理论机制和干预靶点。

It is a vicious circle that hyperuricemia could provoke inflammatory infiltration then cause kidney injury, nevertheless, kidney disease also increases serum uric acid level. But the mechanism is not clarified. Our previous research demonstrated that high concentration uric acid promotes ROS generation from mitochondrial of endothelial then active the inflammasome, and high concentration uric acid increased LncRNA-HOTAIR in the glomeruli endothelial cell then absorb miR-22 to promote the direct target gene NLRP3 expression. Therefore, we hypothesis high concentration would increase NLRP3 expression via HOTAIR and active NLRP3 via ROS by the double pathway, subsequently lead inflammation of renal endothelial cell and the kidney injury. Hence, we will demonstrate the mechanism of HOTAIR promote NLRP3 expression as the sponge of miR-22 and clarify high concentration uric acid induce NLRP3 activation through disaggregation of TXNIP/TRX. To validate the above mechanism using HOTAIR-/- TXNIP-/- mice. These work will provide a novel theory and therapeutic target for clinical diagnosis and treatment of hyperuricemia kidney disease.