成纤维细胞生长因子-21对1型糖尿病肾病的预防作用及其机制探索

Diabetic nephropathy(DN)is the main cause of death in type 1 diabetic patients.P53 induced potocyte apoptosis and the subsequent glomerular injury are considered as the key incentives and pathological features of type 1 DN.Recent study reported that fibroblast growth factor (FGF)-21 significantly prevented type 2 DN without impact on blood glucose level.Since there are differences for the pathological features and FGF21 expression levels between type 1 and type 2 DN, therefore, whether FGF21 also shows directly preventive effect on type 1 DN is still a unknown scientific question.Additionally, we found that FGF21 negtively regulats P53 acitivity in the liver and kidney. An complex comprised of FGF21 and P53 was further detected in the liver tissue. Moreover, P53 activity was appreciated to be indirectly influenced by the downstream target kinises of FGF21. Therefore, we forward a new hypothesis that FGF21 negtively regulates renal P53 activity either by formation of complex with P53 or by activation of its downstream signaling pathways, and finally prevent type 1 DN. In this project a few of gene knock-out mice will be applied, in combination of in vitro mechanistic studies, to verify the protection by FGF21 fromtype 1 DN and the underlying mechanism, which will provide strong scientific evidence for targeting FGF21 to prevent type 1DN in clinics.

糖尿病肾病（DN）是导致1型糖尿病患者死亡的最主要原因，P53活化造成的足细胞死亡和肾小球损伤是1型DN的主要原因和病理特征。研究表明成纤维细胞生长因子（FGF）-21在不影响血糖的前提下能显著抑制2型DN。由于1型和2型DN在病理特征及FGF21表达方面存在差异，因此FGF21是否对1型DN也具有直接的预防作用仍是一个未知的科学问题；更重要的是FGF21保护糖尿病肾病的机制仍不明确。我们发现FGF21对肝，肾P53活性具有负调控作用；同时证实肝脏中存在FGF21与P53的复合物。另外FGF21下游关键激酶也能间接抑制P53的活性。据此我们提出科学假设：在肾脏中FGF21能通过与P53形成复合物的方式或通过激活下游信号途径负调控P53活性从而预防1型DN。我们将引入多种转基因小鼠并配合体外研究解析FGF21对1型DN的保护效应及分子机制。为临床应用FGF21预防1型DN提供科学依据。

本课题的研究主旨是系统考察成纤维细胞生长因子(FGF)21对1型糖尿病肾病的保护作用，同时深入解析FGF21在1型糖尿病小鼠中发挥肾脏保护作用的分子机制，明确p53及其信号通路在该保护机制中的作用。课题组紧紧围绕既定研究目标，密切关注国际、国内研究热点，积极跟踪国际前沿，创造性的完成了如下研究工作:1)证实了外源 FGF21干预能有效预防1型糖尿病诱导的肾病;2)机制探索揭示FGF21是通过激活肾脏AKT进而负调控肾脏中TGF-β-p53-Smad2/3信号通路，阻断由于内皮细胞间充质转化（EMT）诱导的肾脏纤维化，最终发挥对1型DN的预防作用；3)鉴于OVE26小鼠是学界公认研究1型DN最佳的模式动物，本课题组也通过系统性研究证实FGF21干预能改善调控AMPK/Sirt1信号通路从而抑制OVE26小鼠肾脏纤维化改变。机制探索显示这可能与FGF21诱导AMPK/SIRT1信号通路的激活有着密切关系。