持久性有機污染物全氟辛烷磺酸（PFOS）对糖尿病肾病的影响

Diabetic nephropathy (DN) is the leading cause of end stage renal disease. TGF-β signaling pathway plays an important role in the process of development of diabetic nephropathy but how persistent organic pollutants (POP) affects TGF-β signaling pathway during renal injury has not been elucidated. Perfluorooctane sulfonate (PFOS) is one emerging POP in China. PFOS is readily absorbed after oral exposure and accumulates primarily in the serum, kidney, and liver. Toxicological studies on animals indicate its potential developmental, reproductive and systematic effect. A novel and potentially important preliminary finding was that PFOS enhanced expression of markers for fibrosis, inflammation, hypertrophy and oxidative stress in renal tubular epithelial cells during diabetic condition. PFOS also promoted the activation of TGF-β signaling. Dietary intake of PFOS promoted the renal injury in the mouse model of Adriamycin nephropathy. Based on these findings, we hypothesize that PFOS may play an essential role in enhancing renal injury by increasing inflammation, fibrosis, hypertrophy, and oxidative stress during the progression of diabetic nephropathy. To test this hypothesis, we will firstly determine the effects of PFOS in renal fibrosis, hypertrophy, oxidative stress, and inflammation under diabetic condition in vitro. We will then examine how PFOS affects TGF-β signaling and related metabolic pathways under diabetic condition in vitro. Next, we will validate the effects of PFOS on renal injury during DN in type 2 diabetic mouse models. Finally, we will determine the correlation of PFOS levels in serum and urine with occurrence of DN in human patients. This novel study is significant because an identification of the effects of PFOS in DN will identify how an environmental pollutant is associated with renal injury in DN. These findings may suggest the potential health risk to be concerned due to the toxicological effects of PFOS as a ubiquitous compound in the environment.

虽然TGF-β信号通路在糖尿病肾病发展过程中起到重要的作用，但持久性有机污染物会否影响TGF-β信号通路尚未阐明。全氟辛烷磺酸（PFOS）是中国一新兴持久性有机污染物。PFOS在接触后很容易积累在肾脏。本课题组通过对在高糖刺激下，首次发现PFOS加重肾小管上皮细胞纤维化、炎症、氧化应激及细胞肥大，并激活TGF-β信号通路。另外，PFOS促进了在阿霉素肾病小鼠模型肾脏损伤。基于前期研究，我们假设PFOS通过诱发炎症，纤维化、氧化应激和肾脏肥大增加肾脏在糖尿病肾病的损伤。因此，我们将首先确定在体外糖尿病条件下PFOS对肾纤维化，肥大，氧化应激和炎症的影响。并研究PFOS如何影响TGF-β信号机制及相关的代谢途径。更利用2型糖尿病小鼠模型去验证PFOS对肾损伤的影响。最后，将利用糖尿病肾病病人的血液及尿液样本来确定PFOS的水平与糖尿病肾病的相关性。本课题将阐明环境污染物怎样与糖尿病肾病有关。

糖尿病肾病是导致终末期肾病的主要原因，目前仍无有效的治疗方法。虽然TGF-β信号通路在糖尿病肾病发展过程中起到重要的作用，但在肾损伤过程中，持久性有机污染物会否及如何影响TGF-β信号通路尚未阐明。.全氟辛烷磺酸（Perfluorooctane sulfonate, PFOS）是中国一新兴持久性有机污染物作为表面活性剂，它通常用于不粘炊具或防水服。PFOS在口腔接触后很容易被吸收和主要积累在血清，肾脏和肝脏。动物毒理学研究表明它對发育和生殖有負面的影响。.基于前期研究，我们假设在糖尿病条件下，PFOS通过诱发炎症，纤维化、和氧化应激，加重肾脏损伤。.为了验证此假说，我们将首先在体外糖尿病条件下确定PFOS加重肾纤维化，氧化应激和炎症的影响。我们首次发现PFOS加重了肾小管上皮细胞及肾系膜细胞的纤维化、炎症、及氧化应激。我们亦发现在糖尿病状态下，PFOS加重动脉内皮细胞氧化应激，以引致内皮细胞功能损伤，影响大鼠主动脉内皮依赖性舒张。另外，我们验证在2型糖尿病小鼠模型中，PFOS增加肾损伤的程度，加重肾纤维化，氧化应激和炎症。.我们亦利用细胞及动物实验证明PFOS通过调节TGF-β信号通路去加重糖尿病引发的氧化应激，纤维化和炎症，揭示PFOS在糖尿病肾病发病机制中起重要作用及糖尿病肾病病程发展相关性，从而建立环境污染物能够加重糖尿病肾病发生的新思路及机制。.我们首次证明了PFOA和PFOS在糖尿病条件下影响肾系膜细胞及肾脏中的氨基酸生物合成，柠檬酸循环和嘌呤代谢。當培养腎細胞時，补充L-酪氨酸，L-苯丙氨酸，L-精氨酸和L-色氨酸等氨基酸显着降低了在高葡萄糖及PFOA/PFOS同时诱导的纤维化和炎症的指标。这些有改变的代谢物可以成为PFOS影响糖尿病肾病病程发展相关的生物标记物，用以加强对PFOS引致糖尿病肾病之临床诊断和药物毒性研究。.此外，我们还证明了另一种持久性有机污染物BDE-47促进了细胞中脂肪细胞的分化，能促进小鼠肥胖和脂肪肝。.综合地证明在糖尿病条件下PFOS对糖尿病肾病病程发展有密切关系，从而确定环境污染物会加重糖尿病肾病发生的新思路及机制。本研究是对持久性环境污染物与糖尿病肾病的一个初步探索，有助于进一步开展持久性环境污染物与慢性肾脏疾病的研究工作，为开发PFOS的生物检测技术，提供参考依据。