WU Song,DU Yaqin,ZHANG Ping,et al.T0901317 improves renal injury in db/db mice by activating liver X receptor α[J].J Third Mil Med Univ,2020,42(01):75-80.

T0901317激活肝X受体α改善db/db小鼠肾损伤(/HTML )




T0901317 improves renal injury in db/db mice by activating liver X receptor α
吴松杜亚琴 张萍 汪伟 陈莎莎李贵森 王莉丁涵露
WU Song DU Yaqin ZHANG Ping WANG Wei CHEN Shasha LI Guisen WANG Li DING Hanlu

Department of Nephrology, Sichuan Provincial People’s Hospital, Medical School of University of Electronic Science and Technology, Chengdu, Sichuan Province, 610072, China

db/db mice liver X receptor thrombomodulin diabetic nephropathy
R692.9; R966; R977.6

目的 观察肝X受体(liver X receptor,LXR)激动剂T0901317、血栓调节蛋白(thrombomodulin,TM)干扰RNA重组腺病毒Ad-TMshRNA对db/db糖尿病肾病(diabetic nephropathy, DN)小鼠肾损伤的影响。方法12周龄雄性db/db小鼠36只,应用随机数字表法进行分组,分为DN生理盐水组、Ad-ctrl+DN组、Ad-TM shRNA+DN组、T0901317+DN组、Ad-TMshRNA+T0901317+DN组和Ad-ctrl+T090131+DN组,每组6只小鼠。2.5×109 pfu Ad-TMshRNA和Ad-ctrl分别通过尾静脉注射到对应组小鼠,1周后T0901317按0.5 mg/(kg·d)灌胃对应组小鼠且连续给药7 d。4周后,采用 Western blot检测小鼠肾组织LXRα、LXRβ、VCAM-1和ICAM-1表达;检测血肌酐水平,同周龄雄性野生C57BL/6小鼠给予生理盐水胃饲作为正常对照组。结果DN组、Ad-ctrl+DN组较野生小鼠,其肾组织LXRα表达下降(P<0.05),与DN、Ad-ctrl+DN组和Ad-TMshRNA+DN组比较,T0901317+DN组、Ad-TMshRNA+T0901317+DN组、Ad-ctrl+T0901317+DN组小鼠肾组织LXRα表达增加(P<0.05)。DN各组小鼠LXRβ表达较野生鼠下降,T0901317对DN各组小鼠肾组织LXRβ表达无显著影响。DN组、Ad-ctrl+DN组较野生小鼠,血肌酐、肾组织VCAM-1和ICAM-1表达升高、肾组织病理损伤加重(P<0.05),与DN对照组比较,Ad-TMshRNA沉默组小鼠肾组织损伤加重、肾组织VCAM-1和ICAM-1表达增加(P<0.05),而T0901317+DN和Ad-ctrl+T0901317+DN组小鼠肾损伤减轻、VCAM-1和ICAM-1表达减少(P<0.05)。结论T0901317可能通过激活LXRα减少VCAM-1和ICAM-1表达从而改善db/db小鼠肾损伤。


ObjectiveTo determine the effects of liver X receptor (LXR) agonist T0901317 and thrombomodulin (TM) interfering RNA recombinant adenovirus Ad-TM shRNA on renal injury of db/db mice with diabetic nephropathy (DN). MethodsA total of 36 male db/db mice (12 weeks old) were randomly assigned into 6 groups (n=6), DN group, Ad-ctrl+DN group, Ad-TMshRNA+DN group, T0901317+DN group, Ad-TMshRNA+T0901317+DN group and Ad-ctrl+T0901317+DN group. PBS, 2.5×109 pfu Ad-TM shRNA and Ad-ctrl were injected into mice through tail vein to corresponding mice, while 0.5 mg/(kg·d) T0901317 was intragastrically administered to the corresponding mice for 7 consecutive days. After treatment for 4 weeks, the kidney tissues were collected for detecting the expression of LXRα, LXRβ, VCAM-1 and ICAM-1 by Western blotting. The serum creatinine level was also detected in all the mice. Male wild-type C57BL/6 mice at the same age served as normal control. ResultsThe expression of LXRα in kidney tissue was significantly lower in the DN group and Ad-ctrl+DN group than the wild-type mice (P<0.05), but was obviously higher in the T0901317+DN group, the Ad-TMshRNA+T0901317+DN group and the Ad-ctrl+T0901317+DN group than the DN group, Ad-ctrl+DN group and the Ad-TM shRNA+DN group (P<0.05). The expression of LXRβ in DN mice was notably lower than that in the wild-type mice (P<0.05). T0901317 had no significant effect on the LXRβ expression in renal tissue of DN mice. The DN control group and Ad-ctrl+DN group had significantly higher serum level of creatinine and renal expression of VCAM-1 and ICAM-1, and aggravated renal pathological damages when compared with the wild-type mice (P<0.05). When compared with the DN group, Ad-TMshRNA silenced mice groups had severer renal damages and elevated expression of VCAM-1 and ICAM-1 (P<0.05), while the renal damages were alleviated and the expression of VCAM-1 and ICAM-1 were decreased in the T0901317+DN group and the Ad-ctrl+T0901317+DN group (P<0.05). ConclusionT0901317 improves renal injury in db/db mice by activating LXRα to reduce the expression of VCAM-1 and ICAM-1.


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更新日期/Last Update: 2020-01-07