CN112933232A - PGC-1α激活TFEB介导的自噬在制备治疗急性肾损伤的药物中的应用 - Google Patents
PGC-1α激活TFEB介导的自噬在制备治疗急性肾损伤的药物中的应用 Download PDFInfo
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Abstract
本发明涉及生物医药领域，特别涉及PGC‑1α激活TFEB介导的自噬在制备治疗急性肾损伤的药物中的应用。本发明实验结果表明，PGC‑1α小分子激动剂ZLN005可以通过激活TFEB，促进细胞自噬清除受损的线粒体，改善线粒体功能，进而减轻Cisp诱导的AKI损伤。
Description
技术领域
本发明涉及生物医药领域，特别涉及PGC-1α激活TFEB介导的自噬在制备治疗急性肾损伤的药物中的应用。
背景技术
急性肾损伤(Acute kidney injury,AKI)是一种以肾脏排泄功能迅速降低为主要特征的综合症，肾小管细胞的损伤和死亡是AKI的关键病理特征。AKI是临床常见的危重病症，具有很高的发病率和死亡率，目前治疗手段下AKI病死率依然居高不下。顺铂(Cisplatin,Cisp)是临床化疗常用的抗肿瘤药物之一，其中，肾毒性是Cisp的主要副作用，因此，常用于诱导AKI模型的建立及AKI的治疗研究。多项研究表明，Cisp通过多种信号通路和因子诱导肾小管细胞损伤，线粒体功能障碍在Cisp诱导的AKI中的发病机制中起重要作用。ROS的产生，线粒体膜电位下降，线粒体功能受损，最终导致肾脏损伤。
自噬是真核细胞内的一种动态的自我降解过程，通过溶酶体的介导降解受损的线粒体，错误折叠的蛋白质，DNA以及其他细胞器。自噬分为选择性自噬和非选择性自噬，线粒体自噬是选择性自噬的一种，识别受损线粒体并降解，维持线粒体的质量控制。大量研究表明，肾脏的基础性自噬对于维持肾小管稳态具有至关重要的作用。自噬关键基因的缺失或下调会加重氧化应激反应和线粒体损伤，导致肾功能失调，反之，在肾脏缺血再灌注模型中自噬的激活能够通过减少线粒体损伤和ROS的生成保护肾小管细胞。可见，自噬在改善AKI中肾功能失调和线粒体受损方面发挥着重要的作用。
因此，提供一种药物通过激活自噬缓解急性肾损伤具有重要的现实意义。
发明内容
有鉴于此，本发明提供了PGC-1α激活TFEB介导的自噬在制备治疗急性肾损伤的药物中的应用。本发明实验结果表明，PGC-1α小分子激动剂ZLN005可以通过激活TFEB，促进细胞自噬清除受损的线粒体，改善线粒体功能，进而减轻Cisp诱导的AKI损伤。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了PGC-1α的过表达在制备治疗和/或预防肾脏疾病的药物中的应用。
此外，本发明还提供了PGC-1α的转录调节剂在制备治疗和/或预防肾脏疾病的药物中的应用。
在本发明的一些具体实施方案中，所述PGC-1α的转录调节剂包括ZLN005(2-(4-叔丁基苯基)苯丙咪唑)。
在本发明的一些具体实施方案中，所述PGC-1α的转录调节剂通过激活PGC-1α的转录水平进一步激活TFEB介导的自噬清除受损线粒体。
在本发明的一些具体实施方案中，所述PGC-1α的转录调节剂能够改善肾小管上皮细胞的线粒体功能障碍。
在本发明的一些具体实施方案中，所述肾脏疾病包括Cisp诱导的急性肾损伤。
在上述研究的基础上，本发明还提供了治疗和/或预防肾脏疾病的药物，包括PGC-1α的转录调节剂以及药学上可接受的辅料。
在本发明的一些具体实施方案中，所述PGC-1α的转录调节剂包括ZLN005(2-(4-叔丁基苯基)苯丙咪唑)。
在本发明的一些具体实施方案中，所述肾脏疾病包括Cisp诱导的急性肾损伤。
综上所述，本发明实验结果表明，PGC-1α小分子激动剂ZLN005可以通过激活TFEB，促进细胞自噬清除受损的线粒体，改善线粒体功能，进而减轻Cisp诱导的AKI损伤。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示在AKI小鼠模型中PGC-1α的表达下调。C57BL/6单次腹腔注射Cisp(16mg/kg,i.p.)诱导AKI；(A)血清肌酐尿素氮检测；(B)HE和PAS检测；(C)WB检测PGC-1α的表达水平；
图2示PGC-1α改善Cisp诱导的HK2细胞损伤。HK2细胞使用Cisp(2.5μM,5μM,10μM)处理48h；(A)CCK8检测细胞活力；(B)流式检测Cisp诱导HK2细胞凋亡；(C)WB检测凋亡相关蛋白(Bax和Bcl-2)及PGC-1α表达水平；(D)和(E)过表达PGC-1α检测凋亡水平；
图3示在体外，ZLN005对PGC-1的药理激活抑制了Cisp诱导的损伤；ZLN005(10μM)干预Cisp(5μM)处理的HK2细胞；(A)CCK8检测细胞活力；(B)WB检测凋亡相关蛋白(Bax和Bcl-2)及PGC-1α表达水平；(C)流式检测ZLN005对Cisp诱导的细胞凋亡的影响；
图4示口服灌胃ZLN005可预防Cisp诱导的AKI；C57BL/6单次腹腔注射Cisp(16mg/kg,i.p.)诱导AKI，ZLN005(15mg/kg/d,i.g.)干预4天；(A)血清肌酐尿素氮检测；(B)HE和PAS检测；(C)免疫组化检测；(D)WB检测凋亡相关蛋白(Bax和Bcl-2)及PGC-1α表达水平；(E)Tunnel染色检测凋亡；
图5示ZLN005激活PGC-1α抑制Cisp诱导的线粒体受损；(A)和(B)MitoSOX Red检测线粒体ROS；(C)JC-1检测线粒体膜电位；(D)WB检测线粒体相关蛋白(ATP5b和Ndufs4)的表达；(E)ATP试剂盒检测ATP含量；
图6示PGC-1α通过调节TFEB激活自噬；(A)免疫共沉淀实验证明PGC-1α与TFEB存在相互作用；(B)在HCQ存在或不存在的情况下，WB检测Cisp处理的HK2细胞中P62和LC3蛋白的表达水平；(C)Cisp处理的HK2细胞在ZLN005存在或不存在的情况下,WB检测TFEB、P62和lc3蛋白的表达水平；(D)RT-PCR检测ZLN005处理的HK2细胞中P62 mRNA的表达水平；(E)免疫荧光检测线粒体与自噬小体的共定位情况；
图7示沉默TFEB部分破坏了ZLN005对Cisp处理的HK2细胞的保护作用；HK2细胞转染control siRNA和TFEB siRNA 6h,再使用Cisp或ZLN005处理48h；(A)WB检测自噬相关蛋白(TFEB,P62和LC3)表达水平；(B)WB检测线粒体相关蛋白(ATP5b和Ndufs4)表达水平；(C)MitoSOX检测线粒体ROS水平；(D)WB检测凋亡相关蛋白表达水平；(E)流式检测ZLN005对Cisp诱导的细胞凋亡的影响；(F)ATP试剂盒检测ATP含量；
图8示ZLN005通过PGC-1a/TFEB途径减轻Cisp诱导的AKI小鼠的肾损伤；(A)WB检测自噬相关蛋白(TFEB,P62和LC3)表达水平；(B)电镜检测肾小管上皮细胞线粒体形态；(C)WB检测线粒体相关蛋白(ATP5b和Ndufs4)表达水平；(D)MitoSOX Red检测新鲜肾病冻切片线粒体ROS水平。
具体实施方式
本发明公开了PGC-1α激活TFEB介导的自噬在制备治疗急性肾损伤的药物中的应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
PGC-1α(过氧化物酶体增殖物激活受体γ辅激活因子1)是一种多功能辅助活化因子，能够促进线粒体生物合成。在糖尿病肾病和肾纤维化发展进程中PGC-1α的表达明显减少，提示PGC-1α在肾脏保护作用中具有重要作用。在Cisp诱导的AKI中，肾脏近端小管PGC-1α的缺乏加剧肾小管损伤和肾功能失调，然而，不同策略增强PGC-1α的表达，可以有效缓解糖尿病肾病和肾纤维化损伤。在血管平滑肌细胞中，PGC-1α的缺陷会破坏溶酶体功能和自噬通量，更重要的是，PGC-1α通过促进自噬溶酶体重要调节因子TFEB的激活减少亨廷顿舞蹈症中的蛋白质毒性，以上研究表明PGC-1α可能通过TFEB调节自噬水平。
小分子化合物ZLN005(2-(4-叔丁基苯基)苯丙咪唑)是PGC-1α的转录调节因子，通过转录激活骨骼肌中的PGC-1α起到抗糖尿病作用，并且有研究报道ZLN005通过促进SIRT1表达和自噬的激活抑制高糖诱导的心肌细胞损伤。在冠状动脉疾病以及神经退行性疾病中，ZLN005具有潜在的保护作用，然而，ZLN005在Cisp诱导的AKI中的作用仍未有人报道。
因此，本发明用Cisp分别建立了人肾小管上皮细胞(HK2)损伤模型和小鼠AKI模型，并予以ZLN005干预，观察ZLN005能否通过激活PGC-1α的转录水平进一步激活TFEB介导的自噬清除受损线粒体，改善肾小管上皮细胞的线粒体功能障碍，从而缓解Cisp诱导的急性肾损伤。
本发明提供的PGC-1α激活TFEB介导的自噬在制备治疗急性肾损伤的药物中的应用，所用到的原料及试剂均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1PGC-1α在Cisp诱导HK2细胞损伤中的作用研究
体外构建Cisp(5μM，48h)诱导HK2细胞模型，通过CCK8检测细胞活性、Annexin V/PI流式检测细胞凋亡和WB检测凋亡相关蛋白Bax、Bcl2的表达水平变化。随后，通过PGC-1α质粒过表达或小分子激动剂ZLN005激活PGC-1α，通过CCK8检测细胞活性、Annexin V/PI流式检测细胞凋亡和WB检测凋亡相关蛋白Bax、Bcl2的表达水平变化。随后，通过流式检测线粒体ROS、JC-1染色检测线粒体膜电位、ATP试剂盒检测ATP含量等变化。
图2～5的结果表明：
Cisp(5μM，48h)诱导HK2细胞损伤和线粒体功能障碍，主要表现为细胞活性显著下降、线粒体ROS水平升高、线粒体膜电位降低和ATP含量降低。
通过PGC-1α质粒或ZLN005(10μM)过表达PGC-1α，Cisp诱导HK2细胞活性增加，凋亡受到抑制，线粒体ROS水平降低，线粒体膜电位增加和ATP含量增加。
表1
| Figure2-A | Con | Cisp-2.5 | Cisp-5 | Cisp-10 | Cisp-20 |
| 1 | 0.82475 | 0.625637 | 0.377759 | 0.210102 | |
| 1.001174 | 0.836202 | 0.696088 | 0.425665 | 0.216588 | |
| 1.043003 | 0.792942 | 0.506431 | 0.452739 | 0.243297 | |
| 均值 | 1.014725667 | 0.817964667 | 0.609385333 | 0.418721 | 0.223329 |
| 标准误 | 0.024495923 | 0.022414001 | 0.095867262 | 0.037969257 | 0.017594255 |
| Mean±SD | 1.015±0.024 | 0.818±0.022 | 0.609±0.096 | 0.419±0.038 | 0.223±0.018 |
表2
表3
表4
表5
| Figure3-A | Con | Zln | Cisp | C+Z |
| 1 | 1.064882 | 0.501576 | 0.6993696 | |
| 1.000001 | 1.116152 | 0.59 | 0.89198 | |
| 1.02 | 1.03 | 0.625637 | 0.807438 | |
| 均值 | 1.006667 | 1.070344667 | 0.572404333 | 0.799595867 |
| 标准误 | 0.011546717 | 0.043335001 | 0.063874788 | 0.096544372 |
| Mean±SD | 1.007±0.012 | 1.07±0.043 | 0.572±0.064 | 0.71±0.097 |
表6
| Figure3-B | Con | Zln | Cisp | C+Z |
| PGC-1α | 1.007371 | 1.624646 | 0.622287 | 1.070257 |
| 1.017666 | 1.248279 | 0.602322 | 0.866307 | |
| 0.999905 | 1.480735 | 0.736507 | 1.366842 | |
| 均值 | 1.008314 | 1.45122 | 0.653705333 | 1.101135333 |
| 标准误 | 0.008917972 | 0.189911509 | 0.072399843 | 0.251692124 |
| Mean±SD | 1.008±0.009 | 1.451±0.19 | 0.654±0.072 | 1.101±0.252 |
| Bcl-2 | 1.107207 | 1.285348 | 0.686534 | 0.93589 |
| 1.006624 | 1.300324 | 0.52379 | 0.843003 | |
| 1.050662 | 1.37225 | 0.721631 | 0.928416 | |
| 均值 | 1.054831 | 1.319307333 | 0.643985 | 0.902436333 |
| 标准误 | 0.050420932 | 0.046457127 | 0.10556078 | 0.051606259 |
| Mean±SD | 1.055±0.05 | 1.319±0.046 | 0.644±0.106 | 0.902±0.052 |
| Bax | 1.014936 | 0.861538 | 1.49049 | 0.893964 |
| 1.033556 | 0.825439 | 1.853361 | 1.251797 | |
| 1.017631 | 0.889276 | 1.524971 | 0.82846 | |
| 均值 | 1.022041 | 0.858751 | 1.622940667 | 0.991407 |
| 标准误 | 0.010062911 | 0.032009626 | 0.200293241 | 0.227870375 |
| Mean±SD | 1.022±0.01 | 0.859±0.032 | 1.623±0.2 | 0.991±0.228 |
表7
表8
| Figure4-A | NC | Zln | Cisp | C+Z |
| BUN | 28 | 27 | 312 | 84 |
| 30 | 36 | 308 | 130 | |
| 32 | 40 | 138 | 150 | |
| 30 | 36 | 231 | 54 | |
| 21 | 234 | 153 | ||
| 24 | 285 | 75 | ||
| 27 | 198 | 45 | ||
| 均值 | 27.42857143 | 34.75 | 243.7142857 | 98.71428571 |
| 标准误 | 3.823486317 | 5.5 | 63.27378153 | 45.12838828 |
| Mean±SD | 27.429±3.823 | 34.75±5.5 | 243.714±63.274 | 98.714±45.128 |
| Crea | 18 | 15 | 128 | 39 |
| 21 | 24 | 154 | 42 | |
| 20 | 18 | 30 | 18 | |
| 18 | 18 | 96 | 95 | |
| 12 | 75 | 21 | ||
| 12 | 132 | 60 | ||
| 15 | 54 | 24 | ||
| 均值 | 16.57142857 | 18.75 | 95.57142857 | 42.71428571 |
| 标准误 | 3.644957378 | 3.774917218 | 45.17321162 | 27.32345931 |
| Mean±SD | 16.571±3.645 | 18.75±3.775 | 95.571±45.173 | 42.714±27.323 |
表9
表10
| Figure5-B | Con | Zln | Cisp | C+Z |
| 0.284464 | 0.426696 | 5.12035 | 2.130744 | |
| 0.828775 | 0.656455 | 5.073851 | 2.256565 | |
| 1.887309 | 0.218818 | 5.71663 | 2.789934 | |
| 均值 | 1.000182667 | 0.433989667 | 5.303610333 | 2.392414333 |
| 标准误 | 0.815054271 | 0.218909648 | 0.358440334 | 0.349963062 |
| Mean±SD | 1±0.815 | 0.434±0.22 | 5.304±0.358 | 2.392±0.35 |
表11
| Figure5-D | Con | Zln | Cisp | C+Z |
| Ndufs4 | 0.998805 | 0.941505 | 0.798112 | 0.893896 |
| 1.00087621 | 0.960786 | 0.669913 | 0.93 | |
| 1.007556627 | 0.940622 | 0.770381 | 1.076269 | |
| 均值 | 1.002412612 | 0.947637667 | 0.746135333 | 0.966721667 |
| 标准误 | 0.004573636 | 0.011395347 | 0.067450983 | 0.096572969 |
| Mean±SD | 1.002±0.005 | 0.948±0.011 | 0.746±0.067 | 0.967±0.097 |
| ATP5b | 1.08537 | 1.084522 | 0.803641 | 0.893897 |
| 0.997958454 | 0.958249 | 0.675597 | 0.926 | |
| 1.007874925 | 1.113274 | 0.784553 | 1.08785 | |
| 均值 | 1.030401126 | 1.052015 | 0.754597 | 0.969249 |
| 标准误 | 0.047861957 | 0.082466456 | 0.069078491 | 0.103958158 |
| Mean±SD | 1.03±0.048 | 1.052±0.082 | 0.755±0.069 | 0.969±0.104 |
表12
| Figure5-E | Con | Zln | Cisp | C+Z |
| 0.99594 | 1.137721 | 0.726491 | 0.974748 | |
| 1.00404 | 1.145693 | 0.740899 | 0.986378 | |
| 1.012174 | 1.210756 | 0.465401 | 0.90592 | |
| 均值 | 1.004051333 | 1.164723333 | 0.644263667 | 0.955682 |
| 标准误 | 0.008117006 | 0.040064236 | 0.155067043 | 0.043485707 |
| Mean±SD | 1.004±0.008 | 1.165±0.04 | 0.644±0.155 | 0.956±0.043 |
实施例2ZLN005激活自噬在改善Cisp诱导HK2细胞线粒体功能障碍中的研究
首先，通过自噬抑制剂HCQ探究ZLN005对HK2细胞自噬水平的影响；随后，在Cisp诱导的HK2细胞模型中，采用ZLN005进行干预：WB检测HK2细胞自噬水平的变化、免疫荧光检测线粒体与自噬小体的共定位情况、WB检测自噬相关蛋白LC3Ⅱ和P62的变化。
检测ZLN005干预对Cisp诱导的HK2线粒体功能障碍的影响：流式检测线粒体ROS、WB检测线粒体相关蛋白(ATP5b、Ndufs4)的表达变化以及ATP检测等。
图6结果表明：在Cisp诱导HK2细胞的AKI模型中，自噬相关蛋白LC3Ⅱ显著升高、P62显著下降；在加入自噬抑制剂HCQ后，LC3Ⅱ进一步升高，说明Cisp可诱导HK2自噬水平的升高。ZLN005干预后进一步增加自噬标志蛋白LC3Ⅱ的表达，并显著减轻了Cisp诱导的细胞凋亡。ZLN005诱导了HK2细胞P62的升高，这与其转录水平的升高有关。
ZLN005干预下，线粒体自噬相关蛋白表达显著上调，免疫荧光观察到LC3与线粒体共定位增加，说明ZLN005可能激活了线粒体自噬。另外，通过线粒体ROS、膜电位、ATP水平、线粒体形态以及WB检测线粒体相关蛋白结果可以看出，ZLN005显著改善了Cisp诱导的HK2线粒体功能受损。
表13
| Figure6-B | Con | HCQ | Cisp | C+H |
| LC3-II | 1.007757 | 2.601391 | 1.74445 | 4.645133 |
| 1.001798 | 2.578544 | 3.273204 | 6.749454 | |
| 0.998738 | 1.863763 | 1.383516 | 8.345008 | |
| 均值 | 1.002764333 | 2.347899333 | 2.133723333 | 6.579865 |
| 标准误 | 0.004586495 | 0.419429956 | 1.003185168 | 1.855758356 |
| Mean±SD | 1.003±0.005 | 2.35±0.419 | 2.134±1.003 | 6.58±1.856 |
| P62 | 1.044455 | 1.819499 | 0.998823 | 1.547479 |
| 1.055918 | 1.490154 | 0.782479 | 1.052327 | |
| 1.000449 | 1.511664 | 0.768597 | 1.165912 | |
| 1.00283 | 1.797172 | 0.933237 | 1.413504 | |
| 均值 | 1.025913 | 1.65462225 | 0.870784 | 1.2948055 |
| 标准误 | 0.028433232 | 0.177943475 | 0.113334782 | 0.226084489 |
| Mean±SD | 1.026±0.028 | 1.655±0.178 | 0.871±0.113 | 1.295±0.226 |
表14
| Figure6-C | Con | Zln | Cisp | C+Z |
| P62 | 1.007202 | 1.196402 | 0.66717 | 0.860225 |
| 0.98723278 | 1.305503 | 0.697688 | 1.047792 | |
| 0.995349898 | 1.033158 | 0.485389 | 0.829339 | |
| 均值 | 0.996594893 | 1.178354333 | 0.616749 | 0.912452 |
| 标准误 | 0.010042656 | 0.137066548 | 0.114779895 | 0.118220865 |
| Mean±SD | 0.997±0.01 | 1.178±0.137 | 0.617±0.115 | 0.912±0.118 |
| TFEB | 1.097683 | 1.221211 | 0.715836 | 1.207961 |
| 0.977484092 | 1.380025 | 0.586259 | 1.22964 | |
| 1.006188742 | 1.150948 | 0.750149175 | 1.089477 | |
| 均值 | 1.027118611 | 1.250728 | 0.684081392 | 1.175692667 |
| 标准误 | 0.062773314 | 0.117356329 | 0.086436472 | 0.075447668 |
| Mean±SD | 1.027±0.063 | 1.251±0.117 | 0.684±0.086 | 1.176±0.075 |
| LC3-II | 1.003323 | 1.078433 | 1.36904 | 1.690209 |
| 1.109652468 | 1.525462 | 1.589289 | 1.780374 | |
| 1.025006121 | 1.583074 | 1.59025 | 2.02394 | |
| 均值 | 1.045993863 | 1.395656333 | 1.516193 | 1.831507667 |
| 标准误 | 0.056185878 | 0.276229557 | 0.127439142 | 0.17264149 |
| Mean±SD | 1.046±0.056 | 1.396±0.276 | 1.516±0.127 | 1.832±0.173 |
表15
| Figure6-D | Con | Zln |
| Mean±SD | 1±0.041 | 1.279±0.073 |
实施例3TFEB调控自噬在ZLN005改善Cisp诱导HK2细胞线粒体功能障碍中的研究
通过RNA干扰技术对HK2细胞TFEB的表达进行沉默，综合评估HK2细胞自噬、线粒体功能和凋亡等能力，探讨ZLN005对Cisp诱导的HK2损伤修复是否依赖TFEB活化清除受损线粒体。
图7结果表明：通过免疫共沉淀实验证明了PGC-1α与TFEB存在相互作用，通过ZLN005激活PGC-1α的表达能够上调TFEB表达水平，进一步促进自噬，改善Cisp诱导的线粒体失功。沉默TFEB后，ZLN005对Cisp诱导的细胞损伤改善作用消失。
表16
表17
表18
表19
表20
表21
实施例4Cisp诱导小鼠AKI模型的建立
Cisp溶液配制：生理盐水配制Cisp溶液。C57 BL/6小鼠采用Cisp(16mg/kg)单次腹腔注射建立AKI小鼠模型。四天后取材，检测小鼠血生化，通过HE和PAS染色检测肾脏组织的病理改变，通过WB检测小鼠肾脏组织自噬水平的变化。
生化检测结果(如图1所示)显示，Cisp造模四天后肌酐和尿素氮水平都显著上升，HE和PAS结果显示肾小管上皮细胞脱落，肾小管出现大面积坏死。免疫组化结果显示，在AKI模型组中，PGC-1α表达含量明显降低，肾小管损伤指标Kim-1表达显著增加。WB结果显示，AKI模型组中促凋亡蛋白Bax显著增加，抗凋亡蛋白Bcl2显著减少。肾脏组织自噬水平检测显示，与NC组相比，AKI模型组中LC3Ⅱ表达水平升高。
表22
实施例5口服灌胃ZLN005对Cisp诱导小鼠AKI损伤的干预作用
小鼠体内实验分为三组：正常对照组(NC)、AKI模型组(AKI)、ZLN005治疗组(Cisp+ZLN005)。ZLN005溶液配制：先用DMSO配制ZLN005原液，再用水缓冲液稀释，最终DMSO浓度不超过1％。AKI小鼠采用Cisp(16mg/kg)单次腹腔注射造模。造模当天开始给予ZLN005(15mg/kg，i.g.)干预4天，总共治疗4次。在造模第5天处死小鼠取材，检测小鼠血生化、病理改变、电镜检测线粒体功能、WB检测自噬以及凋亡等相关指标。
通过病理和生化指标检测发现(如图8所示)，与AKI组相比，Cisp+ZLN005组小鼠肾脏病理损伤明显减轻，血肌酐和尿素氮水平显著降低。此外，通过TUNNEL染色结果及WB检测凋亡相关蛋白(Bcl-2和Bax)说明，ZLN005干预显著降低了AKI中肾脏细胞的凋亡水平。通过WB检测自噬相关蛋白LC3Ⅱ和TFEB的表达，AKI组LC3Ⅱ水平升高，但是其TFEB水平显著下降；ZLN005干预后LC3Ⅱ和TFEB的表达也升高，说明ZLN005提高了AKI小鼠肾脏自噬水平。肾脏线粒体生物功能的检测：电镜结果显示AKI小鼠中肾小管上皮细胞线粒体呈片段化的球状，ZLN005治疗组中线粒体呈椭圆形。此外，ZLN005干预也显著抑制了AKI小鼠肾脏线粒体相关蛋白(ATP5b和Ndufs4)的减少。同时，通过新鲜组织冰冻切片检测线粒体ROS发现，AKI组肾脏线粒体ROS水平较高，ZLN005干预后线粒体ROS水平降低。
表23
表24
| Figure8-C | NC | Cisp | C+Z |
| ATP5b | 0.91101 | 0.721751 | 1.097883 |
| 1.042317 | 0.765447 | 1.017068 | |
| 1.046673 | 0.69028 | 0.698434 | |
| 均值 | 1 | 0.725826 | 0.937795 |
| 标准误 | 0.077098371 | 0.037748824 | 0.2111943 |
| Mean±SD | 1±0.077 | 0.726±0.038 | 0.938±0.21 |
| Ndufs4 | 0.926939 | 0.648424 | 0.758758 |
| 1.132435 | 0.453867 | 0.6384 | |
| 0.940627 | 0.523738 | 0.573022 | |
| 均值 | 1.000000333 | 0.542009667 | 0.656726667 |
| 标准误 | 0.114895805 | 0.098557074 | 0.094214465 |
| Mean±SD | 1±0.115 | 0.542±0.099 | 0.657±0.094 |
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (9)
1.PGC-1α的过表达在制备治疗和/或预防肾脏疾病的药物中的应用。
2.PGC-1α的转录调节剂在制备治疗和/或预防肾脏疾病的药物中的应用。
3.如权利要求2所述的应用，其特征在于，所述PGC-1α的转录调节剂包括ZLN005(2-(4-叔丁基苯基)苯丙咪唑)。
4.如权利要求2或3所述的应用，其特征在于，所述PGC-1α的转录调节剂通过激活PGC-1α的转录水平进一步激活TFEB介导的自噬清除受损线粒体。
5.如权利要求2至4任一项所述的应用，其特征在于，所述PGC-1α的转录调节剂能够改善肾小管上皮细胞的线粒体功能障碍。
6.如权利要求2至5任一项所述的应用，其特征在于，所述肾脏疾病包括Cisp诱导的急性肾损伤。
7.治疗和/或预防肾脏疾病的药物，其特征在于，包括PGC-1α的转录调节剂以及药学上可接受的辅料。
8.如权利要求7所述的药物，其特征在于，所述PGC-1α的转录调节剂包括ZLN005(2-(4-叔丁基苯基)苯丙咪唑)。
9.如权利要求7或8所述的药物，其特征在于，所述肾脏疾病包括Cisp诱导的急性肾损伤。
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104873500A (zh) * | 2015-04-29 | 2015-09-02 | 中国人民解放军第四军医大学 | 化合物zln005的用途 |
| CN105073119A (zh) * | 2013-01-23 | 2015-11-18 | 司菲埃拉制药私人有限公司 | 用于线粒体生物发生和与线粒体功能障碍或耗竭相关的疾病的新颖11β-羟基类固醇化合物 |
| KR20180116947A (ko) * | 2017-04-18 | 2018-10-26 | 전남대학교산학협력단 | 급성신장질환 예방, 개선 또는 치료용 조성물 |
| CN108884053A (zh) * | 2015-12-15 | 2018-11-23 | 斯坦福大学托管董事会 | 预防和/或治疗与衰老有关的认知障碍和神经炎症的方法 |
| WO2020033359A1 (en) * | 2018-08-06 | 2020-02-13 | The Board Of Trustees Of The Leland Stanford Junior University | 2-arylbenzimidazoles as ppargc1a activators for treating neurodegenerative diseases |
| CN111499762A (zh) * | 2019-01-31 | 2020-08-07 | 四川大学华西医院 | 一种包含PDGFRβ特异性亲和体和TNFα的融合蛋白及其用途 |
| CN111973595A (zh) * | 2019-05-23 | 2020-11-24 | 南京医科大学第二附属医院 | A939572在制备用于减轻急性肾损伤的药物中的应用 |
| CN112494482A (zh) * | 2020-11-23 | 2021-03-16 | 湘南学院 | 一种宽缨酮在制备预防和治疗急性肾损伤药物中的用途 |
-
2021
- 2021-02-02 CN CN202110140570.0A patent/CN112933232A/zh active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105073119A (zh) * | 2013-01-23 | 2015-11-18 | 司菲埃拉制药私人有限公司 | 用于线粒体生物发生和与线粒体功能障碍或耗竭相关的疾病的新颖11β-羟基类固醇化合物 |
| CN104873500A (zh) * | 2015-04-29 | 2015-09-02 | 中国人民解放军第四军医大学 | 化合物zln005的用途 |
| CN108884053A (zh) * | 2015-12-15 | 2018-11-23 | 斯坦福大学托管董事会 | 预防和/或治疗与衰老有关的认知障碍和神经炎症的方法 |
| KR20180116947A (ko) * | 2017-04-18 | 2018-10-26 | 전남대학교산학협력단 | 급성신장질환 예방, 개선 또는 치료용 조성물 |
| WO2020033359A1 (en) * | 2018-08-06 | 2020-02-13 | The Board Of Trustees Of The Leland Stanford Junior University | 2-arylbenzimidazoles as ppargc1a activators for treating neurodegenerative diseases |
| CN111499762A (zh) * | 2019-01-31 | 2020-08-07 | 四川大学华西医院 | 一种包含PDGFRβ特异性亲和体和TNFα的融合蛋白及其用途 |
| CN111973595A (zh) * | 2019-05-23 | 2020-11-24 | 南京医科大学第二附属医院 | A939572在制备用于减轻急性肾损伤的药物中的应用 |
| CN112494482A (zh) * | 2020-11-23 | 2021-03-16 | 湘南学院 | 一种宽缨酮在制备预防和治疗急性肾损伤药物中的用途 |
Non-Patent Citations (1)
| Title |
|---|
| LONGHUI YUAN，等: "PGC1α alleviates mitochondrial dysfunction via TFEB-mediated autophagy in acutekidney injury mice", 《THE FASEB JOURNAL》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023244685A1 (en) * | 2022-06-14 | 2023-12-21 | Tranquis Therapeutics, Inc. | Treatment of aging-related changes and diseases |
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