双酚A调控足细胞自噬促进糖尿病肾病发生的机制研究

In recent years, the relationships between environmental pollutants and DKD are gaining increasing attention. However, most studies are cross-sectional, which could not fully clarify whether there is a causal relationship between environmental pollutants and DKD. Bisphenol A ( BPA ) is a commonly used plasticizer, which widely exists in the daily necessities. Our group, for the first time, reported an association between the serum BPA levels and increased risks of DKD in a prospective study. Further preliminary studies were conducted in kidney tissue from patients of DKD patients, diabetic mice models and cultured podocytes, and the results showed that: 1 ) the severity of glomerular sclerosis increased with the serum levels of BPA in patients with DKD; 2 ) BPA aggravated the DKD in diabetic mice ; 3 ) BPA caused damages in podocytes, accompanied with the suppression of autophagy, while the action of BPA was reversed by the inhibitor of estrogen receptor. Besides, previous studies have reported that impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Taken together, we proposed the hypothesis: BPA inhibited the autophagy in podocytes through activating the estrogen receptor, which impaired podocytes and aggravate the DKD. This study explore the molecular mechanism of DKD from an environmental perspective, which might be of great importance to the prevention of DKD.

近年来，环境污染物与糖尿病肾病（DKD）的关系受到关注，但现有的研究多为横断面研究，不能完全阐明环境污染物与DKD之间是否具有因果关系。双酚A（BPA）是一种常用的塑化剂，广泛存在于日常生活用品中。课题组采用前瞻性队列研究首次报道了BPA与DKD的发病风险增加有关，并进一步从DKD患者肾脏组织、糖尿病小鼠模型、体外培养的足细胞三个层面开展预实验，结果提示：1）DKD患者肾小球硬化程度随血清BPA水平增加而加重；2）BPA促进糖尿病小鼠DKD的发生；3）BPA损伤足细胞的同时伴随细胞自噬的抑制，且雌激素受体抑制剂可减弱BPA对足细胞自噬的干扰。结合既往研究报道：足细胞自噬抑制促进DKD发生，提出假设：BPA通过作用于雌激素受体，加重高糖状态下的足细胞自噬紊乱，进而损伤足细胞，促进DKD的发生。本研究从环境因素入手，探讨DKD发生的分子机制，对改善DKD的防治有重要意义。

近年来，环境污染物与糖尿病肾病（DKD）的关系受到关注。双酚A（BPA）是一种常用的塑化剂，广泛存在于日常生活用品中。课题组前瞻性队列研究发现BPA暴露与DKD的发病风险增加有关，但BPA加重DKD的机制尚不明确。足细胞损伤是DKD发病的关键环节。本研究利用不同浓度的BPA干预小鼠，明确了BPA对足细胞损伤的作用。在研究过程中我们发现，BPA主要通过诱导NETs释放引起足细胞损伤。我们通过利用Dnase I清除NETs或PAD4敲除阻断NETs产生，阐明了BPA诱导的NETs在DKD中的作用。本研究从环境因素入手，探讨DKD发生的分子机制，对改善DKD的防治有重要意义。