Clusterin对慢性肾衰竭并发心脏瓣膜钙化的影响及作用机制研究

Cardiovascular disease is the main death cause of chronic renal failure patients. Cardiac valve calcification is the important manifestation of chronic renal failure patients with cardiovascular complications,but the exact mechanisms are unknown. Clusterin (CLU) has been confirmed to play a protective role in the prevention and treatment of cardiovascular disease which may be related to inflammatory cytokines. On the basis of long-term follow-up,our preliminary study found patients with cardiac valve calcification had lower level of CLU expression than those withnot cardiac valve calcification by two-dimensional gel electrophoresis combined mass spectrometry,and this result had been confirmed by Western Blot. Uremic rats with cardiac valve calcification had lower level of CLU expression in serum but higher level in valves than control group.Therefore we speculate CLU may has a protective role in the process of cardiac valve calcification in chronic renal failure patients. This research will investigate the effect and mechanism of CLU on chronic renal failure complicated with cardiac valve calcification by 5/6 nephrectomy combined with high phosphorus diet animal model and valvular interstitial cell culture model, evaluate the relation between CLU expression and cardiac valve calcification degree in vivo, observe the effects of CLU on valvular interstitial cell calcification and inflammatory cytokines expression in vitro. This research will help to clarify the mechanisms of cardiac valve calcification in chronic renal failure patients, have important clinical significance.

心血管疾病是慢性肾衰竭患者的主要死因，心脏瓣膜钙化是慢性肾衰竭心血管疾病的主要表现，但其机制及影响因素尚不明确。有报道丛生蛋白（CLU）在心血管疾病中起保护作用，其作用与炎症细胞因子相关，我们的前期工作发现心脏瓣膜钙化的肾衰竭患者血清CLU明显低于无钙化组，而出现瓣膜钙化的尿毒症大鼠血清CLU表达降低，但瓣膜组织中CLU表达高于对照组，因此我们推测CLU可能在慢性肾衰竭患者心脏瓣膜钙化过程中起保护作用。本研究拟在前期基础上，利用诱导慢性肾衰竭动物模型评价CLU表达与瓣膜钙化程度的相关性及与炎症细胞因子表达的关系，利用瓣膜间质细胞原代培养及钙化诱导模型，通过基因修饰观察干预CLU表达对瓣膜间质细胞钙化及炎症细胞因子表达的影响，进一步利用慢性肾衰竭大鼠血清培养细胞并行CLU基因修饰，在体外模拟肾衰竭环境验证CLU在慢性肾衰竭心脏瓣膜钙化过程中的作用，为临床提供新的预防及治疗思路。