非诺贝特通过 SIRT1/NF-κB 信号通路对大鼠糖尿病视网膜病变的影响。
Effect of fenofibrate on diabetic retinopathy in rats via SIRT1/NF-κB signaling pathway.
机构信息
Department of Ophthalmology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China.
出版信息
Eur Rev Med Pharmacol Sci. 2019 Oct;23(19):8630-8636. doi: 10.26355/eurrev_201910_19180.
OBJECTIVE
To explore the influence of fenofibrate on the diabetic retinopathy (DR) in rats via the sirtuin1 (SIRT1)/nuclear factor-κB (NF-κB) signaling pathway.
PATIENTS AND METHODS
A total of 30 SD rats were divided into group A (DR group), group B (fenofibrate treatment group) and group C (Healthy group). Rats in group A were intraperitoneally injected with 50 mg/kg streptozotocin (STZ) for 5 days without feeding. After fasting for 2 days, blood was drawn from the tail veins of the rats to measure blood glucose, and blood glucose ≥16.7 mmol/L represented that the model was eligible. Those in group B were injected with STZ and nourished with the mixed feed containing fenofibrate (10 mg/kg). Those in group C were intraperitoneally injected with normal saline and set as negative control group. The retinal structure of rats in the three groups was observed via immunohistochemical staining, and the apoptosis of retinal ganglion cells (RGCs) was evaluated via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Moreover, the protein expressions of Sirtuin1 (SIRT1) and NF-κB were detected using immunofluorescence assay and Western blotting.
RESULTS
According to the immunohistochemical staining results, rats in group C had intact retinal nuclear layer tissues without phenomena such as fracture, disorderly arrangement, blur structures, and nerve fiber layer edema. Those in group A exhibited fracture of retinal nuclear layer tissues, disorderly arranged cells, blur retinal structures at all layers, and a quite evident nerve fiber layer edema. Compared to that in group A, the nerve fiber layer edema in group B was significantly improved. The TUNEL assay results revealed that compared to normal rats in group C, those in group A and group B had apoptotic RGCs. Additionally, the number of apoptotic cells was the largest in group A, and compared to that in group A, it was notably reduced in group B after treatment with fenofibrate. According to the immunofluorescence assay results, after being treated with fenofibrate, rats in group B showed a significantly lower protein expression level of NF-κB in the retina than in group A. Based on the Western blotting detection results, the protein expression level of NF-κB in group B was evidently lower than that in group A, and was the highest in group A and the lowest in group C. Compared to that in group C, the protein expression level of SIRT1 in group B was increased.
CONCLUSIONS
Fenofibrate facilitates the expression of SIRT1 in the retinal tissues to reduce the NF-κB activity, thereby treating DR in rats.
目的
通过沉默信息调节因子 1（SIRT1）/核因子-κB（NF-κB）信号通路探讨非诺贝特对糖尿病大鼠视网膜病变（DR）的影响。
方法
30 只 SD 大鼠分为 A 组（DR 组）、B 组（非诺贝特治疗组）和 C 组（健康组）。A 组大鼠连续 5 天腹腔注射 50mg/kg 链脲佐菌素（STZ），不喂食。禁食 2 天后，从大鼠尾静脉采血，检测血糖，血糖≥16.7mmol/L 表示模型合格。B 组大鼠腹腔注射 STZ，同时给予含非诺贝特（10mg/kg）的混合饲料。C 组大鼠腹腔注射生理盐水，作为阴性对照组。通过免疫组化染色观察三组大鼠视网膜结构，通过末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记（TUNEL）法评估视网膜神经节细胞（RGC）凋亡。此外，采用免疫荧光法和 Western blot 法检测 Sirtuin1（SIRT1）和 NF-κB 的蛋白表达。
结果
根据免疫组化染色结果，C 组大鼠视网膜核层组织完整，无断裂、排列紊乱、结构模糊、神经纤维层水肿等现象。A 组大鼠视网膜核层组织断裂，细胞排列紊乱，各层视网膜结构模糊，神经纤维层水肿明显。与 A 组相比，B 组神经纤维层水肿明显改善。TUNEL 检测结果显示，与正常 C 组大鼠相比，A 组和 B 组 RGC 均发生凋亡。此外，A 组细胞凋亡数量最多，与 A 组相比，B 组经非诺贝特治疗后细胞凋亡数量明显减少。根据免疫荧光检测结果，B 组大鼠视网膜 NF-κB 蛋白表达水平明显低于 A 组。基于 Western blot 检测结果，B 组 NF-κB 蛋白表达水平明显低于 A 组，A 组最高，C 组最低。与 C 组相比，B 组 SIRT1 蛋白表达水平升高。
结论
非诺贝特促进视网膜组织 SIRT1 的表达，降低 NF-κB 的活性，从而治疗大鼠 DR。
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