A-485通过抑制P300/CBP诱导的H3K18ac/H3K27ac减轻糖尿病肾小管细胞脂质沉积  

A-485 alleviates tubular lipid accumulation by inhibiting H3K18ac/H3K27ac induced by P300/CBP in diabetic mice

作　　者：孟丽 朱艳 杨琰 吴婷[2] 任韫卓[2] 杜林珊 曾士洁 杜春阳[2] MENG Li;ZHU Yan;YANG Yan;WU Ting;REN Yunzhuo;DU Linshan;ZENG Shijie;DU Chunyang(Laboratorical Center for Electron Microscopy,Hebei Medical University,Shijiazhuang 050017,China;Department of Pathology,Hebei Medical University,Shijiazhuang 050017,China)

机构地区：[1]河北医科大学电镜实验中心,石家庄050017 [2]河北医科大学病理学教研室,石家庄050017

出　　处：《临床与实验病理学杂志》2024年第5期509-514,共6页Chinese Journal of Clinical and Experimental Pathology

基　　金：国家自然科学基金青年基金(82000773);河北省高等学校科学技术研究项目青年基金(QN2021104);河北省自然科学基金(H2022206463)。

摘　　要：目的观察A-485对糖尿病小鼠肾小管损伤的保护作用及机制。方法将18只雄性C57BL/6J小鼠随机分为对照组、糖尿病肾病(diabetic kidney disease,DKD)组和A-485治疗组。DKD小鼠模型构建采用高脂饲料饲喂8周联合腹腔注射链脲佐菌素5天的方法。随后,A-485治疗组隔日给予1次A-485(10 mg/kg)腹腔注射,共4周。治疗结束后,检测小鼠肾功能、P300酶活性及脂质沉积情况;Western blot法检测SREBP-1、FASN、ACC、ChREBP、P300、CBP、H3K18ac和H3K27ac蛋白的表达水平。结果与对照小鼠相比,DKD小鼠FBG(2.52倍)、BUN(2.89倍)、Scr(2.13倍)及UAE(4.21倍)显著升高(P<0.01);A-485干预能够降低BUN(0.511倍)、Scr(0.636倍)及UAE(0.574倍)的水平(P<0.01)。电镜及油红O染色结果显示,A-485干预抑制糖尿病小鼠肾小管细胞内脂滴形成及SREBP-1(0.544倍)、FASN(0.449倍)、ACC(0.306倍)、ChREBP(0.317倍)蛋白高表达(P<0.01)。同时,A-485干预下调P300酶活性(0.546倍),抑制H3K18ac(0.337倍)和H3K27ac(0.308倍)的表达(P<0.01)。结论A-485能够明显改善糖尿病小鼠肾组织脂代谢紊乱,该作用可能是通过抑制P300诱导的H3K18ac和H3K27ac实现的。Purpose To investigate the protective effect and mechanism of A-485 on renal tubular injury in diabetic mice.Methods Eighteen male C57BL/6J mice were randomly divided into three groups:Control group,diabetic kidney disease(DKD)group and A-485 treatment group.The DKD mice model was established by feeding high-fat diet for 8 weeks and intraperitoneal injection of streptozotocin for 5 days.Subsequently,the A-485 treatment group was given A-485(10 mg/kg/day)by intraperitoneal injection every other day for 4 weeks.After treatment,the renal function,P300 enzyme activity and lipid deposition in renal tissue were measured.Western blot analysis was performed to detect SREBP-1,FASN,ACC,ChREBP,P300,CBP,H3K18ac and H3K27ac protein levels.Results Compared with control mice,the levels of FBG,BUN,Scr and UAE were significantly increased in diabetic mice(FBG:2.52 times,BUN:2.89 times,Scr:2.13 times,UAE:4.21 times),while diabetic mice treatment with A-485 exhibited a remarkable decrease on BUN,Scr and UAE(BUN:0.511 times,Scr:0.636 times,UAE:0.574 times,P<0.01).The results of the transmission electron microscopy and oil red O staining showed that A-485 treatment prevents lipid droplets formation and up-regulation of SREBP-1,FASN,ACC and ChREBP in renal tubular cells of diabetic mice(SREBP-1:0.544 times,FASN:0.449 times,ACC:0.306 times,ChREBP:0.317 times,P<0.01).Furthermore,A-485 intervention downregulated the enzyme activity of P300(0.546 times)and suppressed the expression of H3K18ac(0.337 times)and H3K27ac(0.308 times,P<0.01).Conclusion A-485 can significantly improve renal lipid metabolic disorder in diabetic mice,which may be achieved by inhibiting p300-induced H3K18ac and H3K27ac.

关 键 词：糖尿病肾病 P300/CBP A-485 脂质沉积 乙酰化 

分 类 号：R-332[医药卫生]