蛋白聚糖Syndecan-1在慢性肾脏病基础上急性肾损伤发病中的作用及机制研究

急性肾损伤（AKI）已成为急诊、危重症等学科面临的重大问题，其中慢性肾脏病CKD基础上发生AKI（AonC）更凶险，防治更困难。申请者及团队建立国际上首个心脏术后AKI动态预警系统，并首次发现AKI时Syndecan-1(SDC-1)与肾损伤关系密切，且AonC时相关性更强。SDC-1不但维持细胞结构，而且剪切酶MMP作用下脱落的SDC-1胞外段可参与炎症。我们研究进一步发现：抑制MMP减少低氧诱导的SDC-1脱落，减轻炎症反应。结合我们在AKI低氧、炎症等方面的系列工作，提出科学假设:CKD时肾脏持续低氧使HIF1α高表达并通过MMP9增加SDC-1脱落，诱导炎症反应，使CKD时更易发生AKI。本项目拟从分子、细胞、动物和临床层层深入，以低氧诱导SDC-1脱落为主线，聚焦炎症反应，研究并阐明促发AonC的关键分子机制，并探讨血SDC-1对AonC的预测作用，达到早期识别，改善预后的目的。

Acute kidney injury (AKI) has become a major issue in emergency and critical care medicine, AKI superimposed on chronic kidney disease (CKD) (AonC) is more critical and more difficult to treat. The applicant and his team originally established the clinical dynamic predictive system for cardiac surgery associated AKI, and found the association between Syndecan-1 (SDC-1) and AKI. Moreover, SDC-1 was found strongly correlating with AonC. Not only does SDC-1 maintain the cellular structure, but the ectodomain of SDC-1 shed by matrix metalloproteinase (MMP) may participate in inflammation. Our in-depth study found that inhibition of MMP reduced hypoxia-induced SDC-1 shedding and ameliorated inflammatory response. In combination with our work on AKI hypoxia and inflammation, we propose a scientific hypothesis that sustained renal hypoxia in CKD leads to the high expression of HIF1α and increases the shedding of SDC-1 through MMP9. The shed SDC-1 induces inflammatory response and increases the susceptibility to AKI in CKD individual. This project intends to conduct in-depth studies from the molecular, cellular, animal and clinical levels, regards hypoxia-induced SDC-1 shedding as the common thread, focuses on the inflammatory reaction, investigates and clarifies the key molecular mechanism that promotes AonC, and elucidates the predictive role of serum SDC-1 on AonC, so as to achieve early recognition and prognosis improvement.