青年-老年内环境差异因子IGFBP2影响肾脏纤维化的机制研究

Chronic kidney disease (CKD) has become a major public health concern. China's rapid aging process has made the elderly population be the main body of CKD patients. Renal fibrosis is an important phenotype of aging kidney, and also the morbidity basis of elderly CKD patients. Recent studies have confirmed that the internal milieu has impact on aging organ by tissue remodeling and changing functions. But whether the internal milieu has impact on the development of aging renal fibrosis is unclear. We have identified the difference internal milieu factors between youth – old: insulin-like growth factor binding protein IGFBPs, etc by using high-flux genomics technology in previous studies. This study will innovatively study and research the impacts of IGFBP2 on aging renal fibrosis by heterochronic parabioses of unilateral ureteral obstruction (UUO). And we will do in-depth study of IGFBP2 regulating renal tubular epithelial cells through inter-mesenchymal transdifferentiation (EMT). We aim to find out the key environmental factors and mechanisms of aging renal fibrosis and develop the theory of renal aging, elucidate new targets for prevention and treatment elderly CKD patients and provide new threads for prevention and treatment for elderly CKD patients.

慢性肾脏病（CKD）已经成为重大的公共卫生问题，我国快速的老龄化进程已使老年人成为CKD主体发病人群。肾脏纤维化是衰老肾脏的重要表型，也是老年CKD的发病基础。近年研究证实，机体内环境影响衰老器官的组织重塑和功能，但内环境是否影响衰老肾脏的纤维化发生发展目前尚不清楚。我们前期研究采用高通量组学技术筛选出青年-衰老动物差异性内环境因子（胰岛素样生长因子结合蛋白IGFBPs等）。本项研究将构建连体动物单侧输尿管梗阻模型，首次创新的研究IGFBP对衰老肾脏纤维化发生发展的影响，并深入研究IGFBP2是否通过调控肾小管上皮细胞间充质转分化（EMT）影响肾组织纤维化进程，明确影响衰老肾脏纤维化的关键内环境因子及其机制，丰富肾脏衰老的发生发展理论内涵，阐明老年CKD防治的新靶点，为老年CKD防治提供新思路。

老年人已成为我国慢性肾脏病（CKD）及血液透析的主体发病人群。老年人群CKD发生发展的危险因素仍需要探讨。肾脏纤维化是衰老肾脏的重要表型，也是老年CKD的发病基础。系膜增殖性肾炎（包括IgA肾病及非IgA沉积性系膜增殖性肾炎）是我国导致肾脏硬化，肾脏功能衰竭的主要病因。近年研究证实，机体内环境影响衰老器官的组织重塑和功能，但内环境是否影响衰老肾脏的纤维化发生发展目前尚不清楚。我们前期研究采用高通量组学技术筛选出青年-衰老动物差异性内环境因子：胰岛素样生长因子结合蛋白IGFBP2。1）本研究确定了IGFBP2在青年及老年人体血清、肾脏、肾脏固有细胞的表达及随增龄的变化情况，发现IGFBP2在体内及体外均随衰老而表达增加。2）构建了IGFBP2基因敲除小鼠，在我国导致肾脏纤维化，肾功能衰竭最常见疾病-系膜增殖性肾炎模型中，通过构建基因敲除小鼠与野生型小鼠的系膜增殖性肾炎模型，发现IGFBP2对肾脏系膜细胞炎症刺激增殖有保护作用。3）进一步利用蛋白芯片技术，发现IGFBP2通过调节PI3K和m通路而发挥抑制系膜细胞增殖的作用，进而抑制肾脏纤维化。初步探讨了IGFBP2作为青年-老年差异的内环境因子，在肾脏衰老及疾病状态下发挥的作用，作为老年肾脏纤维化干预的新靶点，为老年 CKD 防治提供新思路。