NAMPT调节慢性肾脏病血管钙化的机制研究

血管钙化常见于慢性肾脏病患者，但其发生机制尚不明确。NAMPT是由内脏脂肪细胞分泌的脂肪因子，具有抗衰老和调控血管重塑的作用。临床资料显示慢性肾脏病患者的血浆NAMPT水平升高，但其是否参与调控血管钙化不明。预实验结果显示：NAMPT抑制血管平滑肌细胞钙化，而使用NAMPT抑制剂FK866可促进血管平滑肌细胞和慢性肾脏病大鼠主动脉钙化，且NAMPT能增加Sirt1的表达水平和降低Notch信号关键分子NICD的水平。因此，我们假定：NAMPT通过上调Sirt1的表达水平，抑制Notch信号的激活，从而抑制慢性肾脏病血管钙化。本课题拟采用血管平滑肌细胞钙化和大鼠慢性肾脏病血管钙化模型，运用腺病毒、基因修饰、RNA干扰等技术方法，从分子、细胞及动物不同的水平探讨NAMPT调节血管钙化的作用，阐明NAMPT抑制血管钙化的Sirt1/Notch信号机制，为慢性肾脏病血管钙化的防治提供新的线索。

Vascular calcification is highly prevalent in patients with chronic kidney disease. However, the mechanism underlying vascular calcification remains unclear. NAMPT is an adipokine secreted by visceral adipocytes. It has anti-aging properties and regulates vascular remodeling. Clinical data show that plasma levels of NAMPT are increased in patients with chronic kidney disease, but it is unclear whether NAMPT regulates vascular calcification. Our preliminary data show that NAMPT inhibited vascular smooth muscle cell calcification, whereas inhibition of NAMPT by FK866 promoted calcification of vascular smooth muscle cells and aortic calcification in rats with chronic kidney disease. In addition, NAMPT increased Sirt1 expression, but decreased Notch signaling key molecule, NICD expression in vascular smooth muscle cells. Based on these findings, we hypothesized that NAMPT inhibits vascular calcification in chronic kidney disease through up-regulation of Sirt1 and inhibition of Notch signaling activation. In this study, we will use in vitro model of vascular smooth muscle cell calcification and rat model of vascular calcification in chronic kidney disease to investigate the role of NAMPT in regulation of vascular calcification, and decipher the molecular mechanisms by which NAMPT regulates vascular calcification via Sirt1/Notch signal at molecular, cellular and animal levels with adenovirus vector, genetic modification, and short interfering RNA techniques, thus providing novel clues for the prevention and treatment of vascular calcification in chronic kidney disease.