Endorepellin对宫内发育迟缓小鼠肾单位数目减少的挽救作用及机制研究

Early fetal development environment play an important role in the occurrence and progress of adult non-infectious diseases. It is a hot issue in perinatal medicine research，and kidney is an important target organ. A large number of cohort studies suggest that intrauterine growth retardation (IUGR) is an important risk factor for the occurrence and progression of CKD in adulthood, while the decrease of nephron endowment is the key mechanism. To explore the way to reverse the nephron endowment in IUGR, and to prevent the occurrence and progress of CKD in early life can significantly reduce the burden of this kind of disease. The current research shows that the increase of cell apoptosis during the development of the kidney is the main mechanism of the decreased nephron endowment of IUGR. In our previous study, the increase of cell apoptosis in the renal region of IUGR offspring (late renal development) was found to be accompanied by a significant decrease in the expression of perlecan. Recent studies have confirmed that the V domain (Endorepellin) of perlecan has inhibitory effects on apoptosis of different kinds of cells. Therefore, the aim of this study is to confirm the effect of Endorepellin on IUGR offspring rats in reducing the number of nephron saved in the late stage of kidney development, and further explore the molecular mechanism of Endorepellin inhibiting the development of renal cell apoptosis by culturing embryo kidney in vitro. Through the above research, it provides a new target for the exploration of the strategy of CKD prevention and control.

胎儿早期发育环境对成年期非感染性疾病的发生及进展具有重要影响作用，是目前围产医学研究的热点问题，其中肾脏是重要的靶器官。队列研究提示宫内发育迟缓（IUGR）是成年后慢性肾脏病（CKD）发生和进展的重要危险因素，肾单位数目减少是关键环节。探索挽救IUGR肾单位数目减少的方法，在生命早期预防CKD的发生及进展可显著降低此类疾病负担。当前研究显示肾脏发育期细胞凋亡增多是IUGR肾单位数目减少的主要机制。我们前期研究发现IUGR仔鼠（肾脏发育晚期）生肾区细胞凋亡增多，伴随串珠素表达量显著降低。研究证实串珠素的第V结构域（Endorepellin）是重要的抑制细胞凋亡分子。因此，本课题拟通过Endorepellin干预IUGR仔鼠证实其在肾脏发育晚期挽救肾单位数目减少的作用，进一步应用体外培养胚肾研究Endorepellin抑制胚肾细胞凋亡的分子机制，为探索CKD防治策略提供新思路和分子靶标。

宫内及生后早期发育环境可通过表观遗传修饰等机制导致机体正常生理和代谢功能的永久改变，使个体生后对慢性非传染性疾病（如高血压、糖尿病、慢性肾脏病等）易感性增加，即“发育程序化”。肾脏是胎儿“发育程序化”的重要靶器官，促进成年期CKD发生和进展，而肾单位数目减少是关键环节。探索挽救肾单位数目减少的方法，可在生命早期降低CKD疾病负担。肾脏发育期细胞凋亡增多是肾单位数目减少的主要机制。课题组前期通过蛋白质组学筛选出串珠素在IUGR肾脏发育晚期表达量显著降低，而串珠素的第V结构域（Endorepellin）在多种类型细胞凋亡中发挥内源性保护作用。本研究首次在IUGR动物模型和体外血清剥夺模型中证实外源性补充Endorepellin可通过提高胚肾的ERK磷酸化水平，抑制下游关键凋亡促进分子bax的转录，进而发挥细胞凋亡抑制作用。通过生后早期体内干预IUGR动物模型，Endorepellin可增加约30%肾单位数目这一核心“肾脏程序化”关键环节，为干预宫内外发育迟缓患儿肾脏发育异常提供创新思路。