LCN2在CKD并发血管钙化中的作用及机制研究

Vascular calcification is a common complication of chronic kidney diseases (CKD). Phenotypic change in vascular smooth muscle cells (VSMCs) was found to be an essential mechanism of vascular calcification. Lipocalin 2 (LCN2) is a novel recognized biomarker in the diagnosis of AKI. Recent studies demonstrated that LCN2 played a role in the pathogenesis of cardiovascular injury, however the effect of LCN2 on CKD-associated vascular calcification has not been studied. Our preliminary data indicated that the expression of LCN2 and nuclear factor erythroid 2-related factor 2 (Nrf2) was significantly decreased after high phosphate treatment in aortic VSMCs, while exogenous LCN2 attenuated phenotypic change and calcification of VSMCs and inhibited the down-regulation of Nrf2, suggesting that LCN2 could attenuate calcification of VSMCs by upregulating Nrf2. Thus we proposed the research hypothesis: Hyperphosphatemia in CKD inhibited the expression of LCN2/Nrf2 pathway and thus increased the production of reactive oxygen species, which induced the initiation and progression of CKD-associated vascular calcification. In the present proposal, employing the CKD patients, animal models and cell models, we will fully investigate the role and mechanism of LCN2 in the pathogenesis of CKD-associated vascular calcification using the genetic and pharmacological strategies. This research work will provide the new insights and potential targets for clinical intervention of vascular calcification and vascular calcification-related diseases.

血管钙化是慢性肾脏病(CKD)常见的并发症之一。研究表明血管平滑肌细胞(VSMCs)表型转化是血管钙化的重要机制。脂质运载蛋白2(LCN2)是新近发现的AKI诊断标志物，然而有研究显示LCN2在心血管损伤等病理过程发挥作用，但在CKD并发血管钙化中的作用还不清楚。预实验结果显示：高磷可导致VSMCs中LCN2和核因子E2相关因子2(Nrf2)表达下降，外源性的LCN2可改善VSMCs的表型转化和钙化，抑制Nrf2的下调，提示LCN2可能通过上调Nrf2改善VSMCs的钙化。因此我们推测：在CKD，高磷等抑制了LCN2/Nrf2通路，活性氧生成增加，最终导致CKD并发血管钙化的发生。本课题拟在临床、动物和细胞水平，通过基因敲除技术和特异性抑制剂/激动剂，深入研究LCN2在CKD并发血管钙化中的作用及机制，为临床干预血管钙化及其相关疾病提供新的靶点。

血管钙化是慢性肾脏病(CKD)常见的并发症之一。研究表明血管平滑肌细胞(VSMCs)表型转化是血管钙化的重要机制。脂质运载蛋白2(LCN2)是新近发现的AKI诊断标志物，然而有研究显示LCN2在心血管损伤等病理过程发挥作用，但在CKD并发血管钙化中的作用还不清楚。我们的研究结果显示：高磷可导致大鼠VSMCs中LCN2表达显著下降，外源性的LCN2重组蛋白可改善VSMCs的表型转化和钙化；文献报道核因子E2相关因子2(Nrf2)是LCN2潜在的作用靶点，我们发现外源性的LCN2重组蛋白会促进VSMCs中Nrf2的表达，而且Nrf2的激动剂CDDO-EA也可以改善VSMCs的表型转化和钙化，提示LCN2可能通过上调Nrf2改善VSMCs的钙化。因此我们推测：在CKD，高磷等抑制了LCN2/Nrf2通路，活性氧生成增加，最终导致CKD并发血管钙化的发生。本课题拟在临床、动物和细胞水平，通过基因敲除技术和特异性抑制剂/激动剂，深入研究LCN2在CKD并发血管钙化中的作用及机制，为临床干预血管钙化及其相关疾病提供新的靶点。