蛋白聚糖Syndecan-1介导容量过负荷诱发心脏术后急性肾损伤进展的分子机制研究

心脏术后急性肾损伤（AKI）发病率高、死亡率高，容量过负荷（PFO）是AKI加重的重要因素。Syndecan-1（SDC-1）是内皮细胞糖萼的重要成分，不仅是炎症反应的第一道屏障，而且其胞外段参与调控炎症反应。PFO可导致内皮糖萼损伤伴SDC-1脱落。我们前期基础研究发现抑制肾脏SDC-1脱落可减轻炎症反应，发挥肾脏保护作用；临床研究证实轻度PFO显著升高心脏术后AKI患者血、尿SDC-1，高血SDC-1组患者更易发生危重AKI且炎症反应更重。因此，我们提出假设：PFO引起内皮细胞SDC-1脱落，通过激发炎症反应诱发心脏术后AKI进展，SDC-1脱落是导致PFO-AKI恶性循环的重要支点。本项目拟在前期原创性工作基础上，从分子、细胞、动物和临床水平层层深入研究，以PFO致SDC-1脱落为主线，聚焦炎症反应，研究并阐明PFO加重心脏术后AKI的重要分子机制，为危重AKI的有效防治提出新策略。

Cardiac surgery associated acute kidney injury (AKI) has high incidence and mortality rate. Percentage of fluid overload (PFO) is an important factor for AKI exacerbation, while the specific molecular mechanism remains unclear. Syndecan-1 (SDC-1), known as an important component in the endothelial cell glycocalyx, not only serves as the first barrier to prevent inflammation, but also regulates inflammatory reaction with its extracellular domain. PFO may damage the endothelial glycocalyx with the increasing of serum and urine SDC-1. Our previous study confirmed that inhibition of SDC-1 shedding after renal ischemia/reperfusion might exert a positive influence on renal protection might through alleviating the inflammation. Our clinical study proved that slight PFO may cause significant increase of serum and urine SDC-1 in patients with AKI stage 1 after cardiac surgery. Severe AKI is more likely to occur in patients with high level serum SDC-1, whose inflammation is much more severe. Therefore, we hypothesize that PFO may lead to the SDC-1 shedding and then aggravate AKI by stimulating inflammation. The SDC-1 shedding is the key point which results in the vicious circle of PFO-progressive AKI. Based on our preliminary work, We will focus on PFO induced SDC-1-shedding and its mediated inflammation from molecular, cellular, animal and clinical levels in this project. The study will classify the mechanism of PFO contributing to AKI progression and provide new strategy for the prevention and treatment of severe AKI.