CN112402430A - 泽泻醇b-23-醋酸酯在预防和治疗急性肾损伤中的应用 - Google Patents
泽泻醇b-23-醋酸酯在预防和治疗急性肾损伤中的应用 Download PDFInfo
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- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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Abstract
本发明属于生物领域，尤其涉及一种FXR激动剂在制备预防和/或治疗肾脏疾病药物中的应用。具体的，本发明公开了FXR激动剂在制备预防和/或治疗肾脏疾病药物中的应用。所述FXR激动剂为泽泻醇B‑23‑醋酸酯。与现有技术相比，本发明首次验证泽泻醇B‑23‑醋酸酯能够缓解急性肾损伤。本发明提供了泽泻醇B‑23‑醋酸酯作为FXR激动剂，具有应用于预防和治疗急性肾损伤的可能性。
Description
技术领域
本发明属于生物领域，具体涉及一种FXR激动剂在制备预防和/或治疗肾脏疾病药物中的应用。
背景技术
肾脏是维持机体内环境稳态的重要器官，其主要功能是***，可将代谢终产物和过剩物质排出体内，并通过调节水和电解质的滤过和重吸收调控尿量和尿液成分，从而维持机体血压及水盐代谢稳态。肾脏发挥***功能、调节水盐代谢并形成尿液的主要结构基础是肾小球和肾小管，血液成分经过肾小球滤过形成原尿，再经过各节段肾小管的重吸收最终形成尿液，肾小球和各节段肾小管的结构和功能的异常将严重扰乱机体内环境稳态，影响人体的健康。急性肾损伤(acute kidney injury，AKI)是由各种病因引起的肾功能急剧下降的临床综合征，表现为肾小球滤过率(glomerular filtration rate，GFR)下降，氮质血症，水、电解质和酸碱平衡紊乱，重者出现多***并发症，是涉及临床多科的常见危重病症。危重AKI死亡率高达30％～80％，存活的AKI患者约50％遗留永久性肾功能减退。全球疾病负担报告提示AKI致死致残率近年逐渐提高，且治疗费用高昂。
研究显示，代谢性核受体激动剂在缓解AKI中发挥重要功能。代谢性核受体是一组与糖、脂和能量代谢密切相关的核受体的通称，主要包括法尼酯衍生物X受体(FXR)、孕烷X受体(PXR)、过氧化物酶体增殖物激活受体(PPARs)、肝X受体(LXR)和维甲酸X受体(RXR)等。这些核受体被内源性小分子代谢产物如脂肪酸、胆汁酸、氧化性胆固醇等配体激活，在胰岛素敏感性、脂肪生成、脂质代谢、能量平衡、血压调节、炎症发生、细胞生长和分化等过程中起着关键的调节作用，倍受领域关注。大量证据表明，代谢性核受体是代谢性疾病的中心调控因子，其功能障碍是引发代谢综合征的主要原因之一，基于核受体寻找重大代谢疾病新型治疗药物将可有效防治重大代谢疾病的发生和发展。
FXR是核受体超家族的一个成员，因其能被超生理水平的法尼酯激活而命名为法尼酯衍生物受体。随后的研究发现生理水平的胆汁酸如鹅去氧胆酸(CDCA)是FXR的内源性配体，因此FXR又称胆汁酸受体(Bile acid receptor，BAR)。大量研究证明FXR的功能不仅局限于在肝脏和小肠调控胆汁酸合成和转运相关分子的表达，也广泛参与了糖脂代谢及细胞增殖等重要生命过程的调节。除肝脏和小肠外，FXR也在心脏、卵巢、胸腺、脾脏和肾脏中广泛表达。
泽泻块根作为一味中医临床常用上品药材，在肾脏疾病治疗中应用广泛。现代医学对肾脏病临床改变的描述，与中医描述的泽泻主治范围“归肾、膀胱经”、利水、渗湿和泄热功效相符。有研究提示泽泻提取混合物及其主要活性成分三萜类化合物具有激动核受体FXR的作用，其中就包括泽泻醇B-23-醋酸酯。
然而泽泻醇B-23-醋酸酯能否用于预防和治疗急性肾损伤疾病还未见报道。
发明内容
本发明的目的在于提供一种可用于预防和治疗急性肾损伤疾病的潜在化合物。
申请人今年研究发现FXR高水平表达在肾脏近端小管和集合管上皮细胞，在其它肾小管节段、肾小球和髓质***也有不同程度的表达，并参与肾脏水盐重吸收，在肾脏内髓高渗状态的建立及维持中发挥重要功能。有研究报道FXR激活可显著改善，而FXR基因缺陷明显加重,小鼠糖尿病肾病的发生和发展。FXR在缓解顺铂及肾脏缺血再灌注诱导的急性肾损伤中发挥保护作用。
因此，进一步研究FXR在肾脏中的生理功能及其在肾脏疾病发生和治疗中的作用，寻找高效低毒靶向激活FXR的天然激动剂，将对深入探究肾脏疾病治疗的新靶点和新药研发具有重要意义。
本发明的具体技术方案如下：
本发明第一个方面公开了一种FXR激动剂在制备预防和/或治疗肾脏疾病药物中的应用。
优选的，所述FXR激动剂为泽泻醇B-23-醋酸酯。
优选的，所述肾脏疾病为急性肾损伤。
优选的，所述药物以FXR激动剂作为活性成分，还包括药学上可接受的辅料。
本发明第二个公开了一种用于预防和/或治疗肾脏疾病的药物，所述药物包括FXR激动剂。
优选的，所述药物以FXR激动剂作为活性成分。
优选的，所述药物的剂型包括：散剂、糊剂、颗粒剂、丸剂、片剂、胶囊剂、冲剂、膏滋、汤剂或注射剂。
在符合本领域常识的基础上，上述各优选条件，可任意组合，而不超出本发明的构思与保护范围。
本发明验证了核受体FXR激动剂泽泻醇B-23-醋酸酯能够预防和治疗急性肾损伤，具体研究方案为利用野生型C57BL/6小鼠证实泻醇B-23-醋酸酯能够缓解急性肾损伤。
为达到上述目的，本发明的一些优选实施例中，采用的具体技术方案如下：
1.肾脏缺血-再灌注诱导的急性肾损伤(RIRI)模型：小鼠术前禁食12h，自由饮水。3％水合氯醛(100μl/10g)腹腔注射麻醉。开放腹腔，可见到肾脏，切除右肾，并迅速用动脉夹夹闭左肾动脉。缺血30min后松开动脉夹，恢复血流，观察肾脏恢复情况。缝合开口,待小鼠清醒后，将其放回洁净笼具后放回饲养室饲养，定期观察小鼠状态及死亡情况并做好记录。对照组不做缺血处理，其他操作相同。再灌注24小时后取材。
2.肾脏功能指标检测：使用商业化试剂盒以及高效液相法分别检测小鼠血清尿素氮和血清/尿肌酐含量，使用荧光探针检测小鼠尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)含量，尿蛋白使用SDS-PAGE聚丙烯酰胺凝胶电泳法检测。
3.肾脏病理改变的检测：使用肾脏损伤标记物1(Kidney injury marker 1,KIM1)免疫组织化学染色,苏木素-伊红(H&E)染色、糖原(PAS)染色和马松染色等常规病理检测技术检测小鼠肾脏切片病理改变。
4.组织和细胞凋亡通路的检测：采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记测定(TUNEL)法检测小鼠肾脏切片细胞TUNEL染色阳性率；采用Western Blot等方法检测肾脏内凋亡相关蛋白(pro-Caspase 3,cleaved-Caspase3,Bcl2和Bax等)的表达水平和活性；
5.组织和细胞氧化应激和内质网应激水平的检测：使用不同商品化检测试剂盒检测氧化应激相关分子(丙二醛MDA、髓过氧物酶MPO、谷胱甘肽巯基转移酶GSH-ST和过氧化氢H2O2等)含量；使用4-羟基壬烯酸(4-HNE)、8-oxo-2’-羟基脱氧鸟苷(8-oxo-dG,8-OXO)和糖调节蛋白(Grp78)抗体进行小鼠肾脏石蜡切片免疫组织化学染色。
6.组织和细胞免疫反应的检测：使用实时定量PCR和ELISA检测方法对炎症相关分子进行定量分析。使用F40/80等抗体进行小鼠肾脏石蜡切片免疫组织化学染色。
本发明相对于现有技术具有如下的显著优点及效果：
本发明首次验证泽泻醇B-23-醋酸酯能够缓解急性肾损伤。本发明提供了泽泻醇B-23-醋酸酯作为FXR激动剂，具有应用于预防和治疗急性肾损伤的可能性。
附图说明
图1为本发明中泽泻醇B-23-醋酸酯(AB23)缓解RIRI导致的肾功能下降的结果示意图(AIMS-26显著改善RIRI诱导上升的BUN(A)、sCr(B)、CCR(C)、尿NAG(D)和尿蛋白(E)；***p<0.001vs Sham，###p<0.001vs RIRI，n＝6)；
图2为本发明中泽泻醇B-23-醋酸酯(AB23)减轻RIRI所致的肾脏结构损伤的结果示意图(其中：A.肾脏石蜡切片H&E染色结果；B.肾脏石蜡切片PAS染色结果；C.肾小管损伤标记物KIM1免疫组化染色结果；D.KIM1免疫组化染色结果半定量统计结果；E.ATN分数统计结果；***p<0.001vs Sham，##p<0.01vs RIRI，n＝6)；
图3为本发明中泽泻醇B-23-醋酸酯(AB23)减轻RIRI导致的细胞凋亡的结果示意图(其中：A.肾脏石蜡切片TUNEL染色结果；B.Caspase 3活性检测结果；C.Western Blot检测细胞凋亡相关蛋白的表达水平；**p<0.01vs Sham，#p<0.05vs RIRI，n＝6)；
图4为本发明中泽泻醇B-23-醋酸酯(AB23)减轻RIRI导致的细胞炎症反应的结果示意图(其中：A.实时定量PCR检测炎症通路相关分子mRNA水平的改变；B.免疫组织化学染色检测巨噬细胞标记物F4/80的表达；*p<0.05，**p<0.01vs.Sham,#p<0.05，##p<0.01vs.RIRI，n＝6)；
图5为本发明中泽泻醇B-23-醋酸酯(AB23)缓解RIRI导致的氧化应激和内质网应激的结果示意图(使用常规生化试剂盒检测肾脏组织中GSH-ST(A)、H2O2(B)和MDA(C)的含量；免疫组织化学染色方法检测氧化应激标记物4-HNE(D)、8-OXO(E)以及内质网应激标记物Grp78(F)的表达；*p<0.05，**p<0.01，***p<0.001vs.Sham，#p<0.05，##p<0.01，###p<0.001vs.RIRI，n＝7-8)。
具体实施方式
下面结合附图和实施例对本发明的技术方案进行详细描述，但并不因此将本发明限制在所述的实施例范围之中。
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。本发明所用试剂和原料均市售可得。
实施例1
本实施例发现泽泻醇B-23-醋酸酯(AB23)能够缓解肾脏缺血-再灌注诱导的急性肾损伤(RIRI)所致肾功能下降。
血清肌酐(serum Creatinine，sCr)和血清尿素氮(Blood Urea Nitrogen，BUN)是临床检验肾功能的常用生化指标，常同蛋白尿一起作为判定患者是否出现急性肾损伤指标。本研究将实验小鼠分为四组，即假手术(Sham)组、假手术给药(Sham+AB23)组、模型(RIRI)组和模型给药(RIRI+AB23)组。
进行假手术的两组(Sham组/Sham+AB23组)小鼠术前4天分别给予DMSO或AB23腹腔注射，第五天进行右侧肾脏切除、左侧肾脏游离35分钟后缝合腹腔；具体的，小鼠按照60mg/kg的剂量腹腔注射AB23，AB23的浓度约为38.85mmol/L。其中，AB23储存于-20℃的条件下，按照所需剂量用精密天平称取四天的AB23用量后，用DMSO溶解到所需浓度，得到AB23溶液。配制的AB23溶液放置于4℃的条件下保存，避免反复冻融。
模型组(RIRI组/RIRI+AB23组)小鼠术前4天分别给予DMSO或AB23腹腔注射，第五天构建肾脏缺血-再灌注损伤模型。术后24小时取血清、尿液和肾脏，检测血清中的sCr和BUN，检测尿液中蛋白质。
结果表明，RIRI组血清尿素氮(图1A)、血清肌酐(图1B)、内生血肌酐清除率(creatinine clearance rate,CCR)(图1C)、尿N-乙酰-β-D-葡萄糖苷酶(NAG)(图1D)和尿蛋白(图1E)水平显著增加，而AB23处理后可以显著改善这些肾功能指标的增加。以上结果提示AB23可以缓解急性肾损伤导致的肾功能下降。
实施例2
本实施例研究泽泻醇B-23-醋酸酯(AB23)减轻肾脏缺血-再灌注诱导的急性肾损伤(RIRI)所致的肾脏结构损伤。
小鼠肾脏石蜡切片进行苏木素-伊红(H&E)染色(图2A)和糖原(PAS)染色(图2B)，结果显示RIRI组肾小管上皮细胞损伤严重，有明显炎症和细胞凋亡、肾小管管腔扩大且管壁变薄，并出现蛋白管型等现象，而AB23可以改善RIRI导致组织细胞状态异常。免疫组织化学染色显示肾损伤标记物肾损伤分子1(Kidney Injury Molecule 1，KIM1)表达明显升高，而AB23可以下调RIRI导致的KIM1表达增高的现象(图2C-D)。急性肾小管坏死分数(acutetubule necrosis score，ATNscore)也提示AB23可以显著缓解RIRI导致的肾脏损伤(图2E)。因此，AB23可以减轻RIRI所致的肾脏结构病理损伤。
实施例3
本实施例研究泽泻醇B-23-醋酸酯(AB23)减轻肾脏缺血-再灌注诱导的急性肾损伤(RIRI)导致的细胞凋亡。
TUNEL染色结果显示RIRI组小鼠肾脏组织中凋亡细胞数目显著增加，AB23可以减少RIRI导致的细胞凋亡(图3A)。荧光探针检测法显示凋亡执行者含半胱氨酸的天冬氨酸蛋白水解酶3(Caspase 3)的活性在RIRI后明显升高，而AB23可以显著下降RIRI导致的Caspase 3活性增加(图3B)。Western Blot结果显示RIRI导致的凋亡相关分子cleaved-Caspase3、Bax和Bcl2表达的改变可以被AB23显著缓解(图3C)。以上结果提示AB23可以逆转凋亡相关分子的表达，抑制细胞程序性死亡，恢复细胞正常生理状态。
实施例4
本实施例研究泽泻醇B-23-醋酸酯(AB23)减轻肾脏缺血-再灌注诱导的急性肾损伤(RIRI)导致的细胞炎症反应：
利用实时定量PCR检测肾脏组织中趋化因子CCL2、CXCL2，粘附因子ICAM1，早期炎症反应因子TNFα、IFNγ，白介素IL2、IL6，以及非特异性炎症反应因子NOS2等相关炎症分子mRNA的表达水平，发现AB23可以显著抑制RIRI组中这些分子的表达升高(图4A)。利用免疫组织化学方法，对巨噬细胞分子标志物小鼠表皮生长因子样激素样受体(EMR1)，也称F4/80，进行染色，发现RIRI组F4/80表达增加，而AB23可以减少RIRI导致的F4/80表达上升(图4B)。以上结果提示AB23可以通过缓解炎症浸润和降低相关炎症分子的表达减轻RIRI导致的炎症反应。
实施例5
本实施例研究泽泻醇B-23-醋酸酯(AB23)缓解肾脏缺血-再灌注诱导的急性肾损伤(RIRI)导致的氧化应激和内质网应激：
利用生化试剂盒对肾组织匀浆中促进活性氧与谷胱甘肽结合的谷胱甘肽巯基转移酶(GSH-ST)(图5A)、活性氧分子过氧化氢(H2O2)(图5B)以及活性氧积累诱发的膜脂质过氧化产物丙二醛(MDA)(图5C)进行检测，RIRI可以诱导GSH-ST、H2O2和MDA的含量升高，而AB23可以显著缓解这些指标的上升。同时，利用免疫组化检测内源性脂质过氧化产物4-羟基壬烯醛(4-HNE)(图5D)、氧自由基灵敏指示剂8-羟基脱氧鸟嘌呤(8-oxo-dG，8-OXO)(图5E)以及内质网应激重要标记物葡萄糖调节蛋白78(Grp78)(图5F)的表达，结果显示RIRI组中这些分子的表达量均显著增加，而AB23明显改善这些分子的表达改变。以上结果提示AB23可以降低RIRI导致的细胞氧化应激和内质网应激的产生。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (7)
1.FXR激动剂在制备预防和/或治疗肾脏疾病药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述FXR激动剂为泽泻醇B-23-醋酸酯。
3.根据权利要求1所述的应用，其特征在于，所述肾脏疾病为急性肾损伤。
4.根据权利要求1所述的应用，其特征在于，所述药物以FXR激动剂作为活性成分，还包括药学上可接受的辅料。
5.一种用于预防和/或治疗肾脏疾病的药物，其特征在于，所述药物包括FXR激动剂。
6.根据权利要求5所述的药物，其特征在于，所述药物以FXR激动剂作为活性成分。
7.根据权利要求5所述的药物，其特征在于，所述药物的剂型包括：散剂、糊剂、颗粒剂、丸剂、片剂、胶囊剂、冲剂、膏滋、汤剂或注射剂。
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