目的 探讨组蛋白乙酰化转移酶（p300）介导过氧化物酶体增殖物激活受体-γ（PPAR-γ）通过脂质过氧化反应影响糖尿病视网膜病变的分子机制。 方法 采用链脲佐菌素腹腔注射方法对65只SD大鼠构建糖尿病模型，余10只SD大鼠同步腹腔注射等量无菌生理盐水记为正常组。将建模成功大鼠随机分为6组，即p300上调组、p300下调组、PPAR-γ上调组、PPAR-γ下调组、空载对照组和模型组。除正常组和模型组（同步经玻璃体注射等量无菌生理盐水）外，各组分别经玻璃体注射pcDNA-p300、si-p300、pcDNA-PPAR-γ、si-PPAR-γ、pcDNA腺病毒溶液。每组各取5只大鼠，Evans blue法检测左眼血-视网膜屏障损伤程度；全自动生化分析仪检测各组脂质［甘油三酯（TG）、胆固醇（TC）、低密度脂蛋白-胆固醇（LDL-C）、高密度脂蛋白-胆固醇（HDL-C）］、过氧化反应指标［超氧化物歧化酶（SOD）活性、丙二醛（MDA）含量和活性氧（ROS）水平］；上述各组5只大鼠取右眼视网膜组织行苏木素-伊红（HE）染色观察病理改变；每组剩余大鼠断头法处死后，实时定量聚合酶链反应（RT-qPCR）检测左眼视网膜组织p300、PPAR-γ、蛋白激酶Cβ（PKCβ）、衔接蛋白p66Shc（P66Shc）信使核糖核酸（mRNA）表达，免疫标记法（Western blot）检测右眼视网膜组织上述蛋白表达和P66Shc磷酸化水平；染色质免疫沉淀技术（ChIP）验证p300靶向PPAR-γ并观察定位情况。 结果 与正常组比较，其余各组Evans blue浓度、白蛋白渗透，血清TG、TC、LDL-C、MDA含量和ROS水平均升高而HDL-C、SOD活性，p300、PPAR-γ、PKCβ、P66Shc表达和P66Shc磷酸化水平均下降（P < 0.05）。与模型组比较，p300下调组p300表达下降（P < 0.05）、p300下调组和PPAR-γ下调组Evans blue浓度、白蛋白渗透，血清TG、TC、LDL-C、MDA含量和ROS水平均升高而HDL-C、SOD活性，PPAR-γ、PKCβ、P66Shc表达和P66Shc磷酸化水平均下降（P < 0.05），p300上调组p300表达升高（P < 0.05）、p300上调组和PPAR-γ上调组Evans blue浓度、白蛋白渗透，血清TG、TC、LDL-C、MDA含量和ROS水平均下降而HDL-C、SOD活性，PPAR-γ、PKCβ、P66Shc表达和P66Shc磷酸化水平均升高（P < 0.05）。p300下调组与PPAR-γ下调组、p300上调组与PPAR-γ上调组、空载对照组与模型组血-视网膜屏障损伤，脂质和过氧化反应指标，PPAR-γ、PKCβ、P66Shc表达和P66Shc磷酸化差异均无统计学意义（P > 0.05）。正常组大鼠视网膜组织无病理改变，模型组和空载对照组可见明显病理改变，p300下调组和PPAR-γ下调组可见严重病理改变，而p300上调组和PPAR-γ上调组病理改变轻微；ChIP证实p300靶向PPAR-γ，且二者均定位于细胞质。 结论 上调p300可正向介导PPAR-γ控制脂质过氧化反应减轻糖尿病视网膜病变，而下调p300可通过抑制PPAR-γ激活脂质过氧化反应促进糖尿病视网膜病变。

Objective To explore the molecular mechanism of histone acetyltransferase （p300） mediated peroxisome proliferator activated receptor-γ（PPAR-γ） influencing diabetes retinopathy through lipid peroxidation. Methods Diabetes models were established in 65 SD rats by intraperitoneal injection of streptozotocin， and the remaining 10 SD rats were simultaneously intraperitoneally injected with an equal amount of sterile physiological saline and recorded as the normal group. The successfully modeled rats were randomly divided into six groups： p300 upregulated group， p300 downregulated group， PPAR-γ upregulated group， PPAR-γ downregulated group， empty control group， and model group. Except for the normal group and the model group （which were simultaneously injected with an equal amount of sterile physiological saline through vitreous injection）， each group was injected with pcDNA-p300， si-p300， pcDNA PPAR-γ， si-PPAR-γ， and pcDNA adenovirus solution through vitreous injection. Five rats were selected from each group， and Evans blue method was used to detect the degree of damage to the left eye blood retinal barrier. The fully automated biochemical analyzer detects lipids in each group， including triglycerides （TG）， cholesterol （TC）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， as well as peroxidation reaction indicators such as superoxide dismutase （SOD） activity， malondialdehyde （MDA） content， and reactive oxygen species （ROS） levels. Five rats from each group were selected to take retinal tissue from their right eyes for hematoxylin eosin （HE） staining to observe pathological changes. After the remaining rats in each group were euthanized by decapitation， real time quantitative polymerase chain reaction （RT-qPCR） was used to detect the expressions of p300， PPAR-γ， protein kinase C β （PKC β）， and adaptor protein p66Shc （P66Shc） messenger RNA （mRNA） in the left eye retinal tissues， and Western blot was used to detect the expression of the aforementioned proteins and the phosphorylation level of P66Shc in the retinal tissues of the right eye. Results Compared with the normal group， the Evans blue concentrations， albumin penetrations， serum TG， TC， LDL-C， MDA contents， and ROS levels increased in all other groups， while HDL-C， SOD activity， p300， PPAR-γ， PKC β， P66Shc expressions， and P66Shc phosphorylation levels decreased （P < 0.05）. Compared with the model group， the p300 downregulated group showed a decrease in p300 expression （P < 0.05）， the Evans blue concentration， albumin permeability， serum TG， TC， LDL-C， MDA contents， and ROS levels were all increased in the p300 downregulated group and PPAR-γ downregulated group， while HDL-C and SOD activity， PPAR-γ， PKC β， P66Shc expression， and P66Shc phosphorylation levels were all decreased （P < 0.05）. The p300 upregulated group showed an increase in p300 expression （P < 0.05）， and the Evans blue concentration， albumin permeability， serum TG， TC， LDL-C， MDA contents， and ROS levels all decreased in the p300 upregulated group and PPAR-γ upregulated group， while HDL-C and SOD activity， PPAR-γ， PKC β， P66Shc expressions， and P66Shc phosphorylation levels all increased （P < 0.05）. There were no statistically significant differences in blood retinal barrier damage， lipid and peroxidation indicators， PPAR-γ， PKC β， P66Shc expression， and P66Shc phosphorylation between the p300 downregulated group and PPAR-γ downregulated group， p300 upregulated group and PPAR-γ upregulated group， unloaded control group and model group （P > 0.05）. Normal group rats showed no pathological changes in retinal tissues， while significant pathological changes were observed in the model group and empty control group. Severe pathological changes were observed in the p300 downregulated group and PPAR-γ downregulated group， while slight pathological changes were observed in the p300 upregulated group and PPAR-γ upregulated group. Conclusion Up-regulation of p300 can positively mediate PPAR-γ to control lipid peroxidation and alleviate diabetes retinopathy， while down-regulation of p300 can promote diabetes retinopathy by inhibiting PPAR-γ to activate lipid peroxidation.