CN112136763A - 一种Manba基因敲除的肾纤维化动物模型及其应用 - Google Patents
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Abstract
本发明提供了一种Manba基因在构建叶酸诱导的小鼠肾纤维化模型的应用，以及应用所述叶酸诱导的小鼠肾纤维化模型筛选治疗和/或预防肾纤维化的药物中的用途。
Description
技术领域
本发明涉及动物模型技术领域，具体为，涉及一种Manba基因敲除的肾纤维化动物模型的构建方法，以及应用所述肾纤维化动物模型筛选治疗和/或预防肾纤维化的药物中的用途。
背景技术
慢性肾脏病(Chronic kidney disease，CKD)是中国乃至全球重要的公共卫生健康问题。肾纤维化是CKD，乃至进展到终末期肾脏病(End Stage Renal Disease,ESRD)后的共同的病理改变。肾脏纤维化的主要特征为肾小管破坏、萎缩，细胞外基质在肾小管间质中过度沉积，最终导致有效肾单位的丧失和肾功能进行性下降。肾纤维化是一个难以逆转的病理过程，目前尚无有效的治疗方法，因此寻找肾脏纤维化的新靶点，对于指导临床、改善CKD预后具有重要意义。
β-甘露糖苷酶基因(Manba基因，小鼠：Ensembl:ENSMUSG00000028164；人类：Ensembl:ENSG00000109323)表达的蛋白为β-甘露糖苷酶(MANBA)。MANBA是一种溶酶体酶，其功能为修剪N-聚糖中的甘露糖，通过水解β-D-甘露糖残基，从而参与蛋白的翻译后调控。缺乏Manba基因的一类疾病称为β-甘露糖苷贮积病，在人群中的临床表现多样。以神经系统报道为主，较严重的可表现为智力障碍、畸形、发育迟滞等。
但是，Manba基因在人或动物肾脏功能以及肾脏病发生发展中的作用目前还未阐明，为了研究该基因在人或动物肾脏功能以及肾脏病发生发展中的作用关系，需要一种在Manba基因敲除背景下肾损伤及损伤后纤维化的动物模型的建立方法，该方法目前也未见报道。
发明内容
为了克服现有技术的不足，本发明的第一个方面，首次构建了敲除Manba基因的动物肾纤维化疾病模型，更为具体地，上述动物肾纤维化疾病模型的构建方法包括如下步骤：
1)杂交得到Manba基因敲除的纯合子动物；
2)向Manba基因敲除的纯合子动物注射有效量的叶酸；
3)获得Manba基因敲除的动物肾纤维化模型。
所述的动物可以为小鼠。
所述的步骤2)中的注射为腹腔注射。
所述的叶酸的注射剂量为200～300μg/g体重，更为优选的，所述的叶酸的注射剂量为250μg/g体重。
所述的叶酸为先溶于碱性缓冲液后，再注射到动物体内。碱性缓冲液可用来碱化尿液，减轻肾小管内叶酸结晶的形成，减轻因为结晶导致的肾小管损伤。更为优选的，所述碱性缓冲液是NaHCO3溶液。最为优选的，所述NaHCO3溶液中NaHCO3和水的重量比是1：40。
本发明的第二个方面，提供一种根据上述构建方法获得的敲除Manba基因的动物肾纤维化疾病模型。
本发明的第三个方面，提供一种根据上述构建方法获得的敲除Manba基因的动物肾纤维化疾病模型在制备或筛选治疗和/或预防肾纤维化的药物中的应用。
本发明的第四个方面，提供一种筛选治疗和/或预防肾纤维化的药物的方法，包括以下步骤：首先采用上述的方法建立敲除Manba基因的动物肾纤维化疾病模型，然后利用制备得到的动物模型筛选对肾纤维化具有治疗和/或预防效果的药物。
本发明的有益效果如下：
本发明在叶酸诱导的肾纤维化动物模型中，通过Manba基因敲除导致明显的肾纤维化，提示Manba为肾纤维化的新靶点。
本发明构建的叶酸诱导的Manba基因敲除(Manba-/-)小鼠肾纤维化模型，可以来做进一步研究Manba基因在肾脏疾病中的作用及机制，更进一步应用于开发治疗和/或预防肾纤维化的药物，具有良好的前景和临床意义。
本发明所述WT小鼠指野生型(Manba+/+，wild-type，WT)小鼠。
本发明所述小鼠的“饲养”方法为：小鼠饲养于SPF级动物房，应用于标准实验鼠饲料(No.5001，TestDiet)饲养。动物房实施温控和12:12小时光暗周期，自由饮水和进食。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
附图说明
附图用来提供对本发明的进一步理解，并且构成说明书的一部分，与本发明的实施例一起用于解释本发明，并不构成对本发明的限制。在附图中：
图1：小鼠基因型检测结果(+/-为Manba基因敲除杂合子，-/-为Manba基因敲除纯合子，+/+为野生型)。
图2：WT和Manba-/-小鼠注射叶酸或对照溶液后纤维化指标改变。
图3：WT和Manba-/-小鼠注射叶酸或对照溶液后PAS染色。
图4：WT和Manba-/-小鼠注射对照溶液或叶酸后胶原染色，*P＝0.0008。
具体实施方式
以下结合附图对本发明的优选实施例进行说明，应当理解，此处所描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明。
实施例1 Manba基因敲除小鼠肾纤维化模型的建立
取Manba全长基因敲除杂合子(Manba gene mutant heterozygous,Manba+/-)C57BL/6小鼠，杂交、繁育后，通过PCR鉴定获得Manba基因敲除纯合子(Manba-/-)小鼠(图1)。
待前述Manba基因敲除纯合子小鼠长到8～10周龄后，对小鼠腹腔内注射由碳酸氢钠缓冲液配制的叶酸(FA)溶液，所述碳酸氢钠缓冲液使用0.5g NaHCO3溶于20ml蒸馏水配制而成，缓冲液浓度以小鼠身体能够适应为宜，FA剂量为250μg/g体重，注射溶液体积参考表1。
表1
实施例2肾纤维化效果比较
1.方法
1.1分组处置
取8-10周龄小鼠各40只，随机分为如下四组，每组10只，做对应处理：
WT+CTL组：野生型小鼠，注射实施例1碳酸氢钠缓冲液；
Manba-/-+CTL组：Manba-/-基因型小鼠，注射实施例1碳酸氢钠缓冲液；
WT+FA组：野生型小鼠，注射实施例1所述叶酸(FA)溶液。
Manba-/-+FA组：Manba-/-基因型小鼠，注射实施例1所述叶酸(FA)溶液，代表本发明的小鼠肾纤维化模型。
上述处理中，注射溶液体积参考表1，FA剂量为250μg/g体重。1周后，处死小鼠，进行如下检测。
1.2肾小管损伤情况检测
使用PAS染色(过碘酸雪夫氏染色)，观察肾小管病理状态。
1.3肾脏胶原含量检测
使用天狼星红胶原染色检测肾脏胶原含量。
2.结果
2.1肾纤维化指标的mRNA结果
qRT-PCR结果显示叶酸诱导的肾纤维化模型中，Manba-/-组与WT组相比，纤连蛋白(FN)、波形蛋白(VM)、前一型胶原α1(pro-col1α1)、前三型胶原α1(pro-col3α1)、转化生长因子(TGF-β1)等纤维化指标的相对mRNA升高程度更加明显(图1)，提示Manba-/-组小鼠在叶酸作用后较WT组小鼠在转录水平表现出更严重的肾纤维化。
2.2肾小管损伤情况检测结果
Manba-/-+CTL组小鼠较WT+CTL组小鼠肾脏未见明显的形态学改变。叶酸作用后，WT+FA组小鼠肾脏可见肾小管上皮细胞变性、脱落和坏死改变。肾小管管腔可见扩张，管腔内有脱落的小管上皮细胞、管型和渗出物。而Manba-/-+FA组小鼠肾小管可见肾小管坏死程度较WT+FA组更严重，管腔扩张更加明显(图2)。表明Manba-/-小鼠在叶酸作用后较WT小鼠出现更严重的肾脏病理改变。
2.3肾脏胶原含量检测结果
WT+FA组小鼠肾脏可见少许胶原成分，较未注射叶酸的组别稍有增加。而Manba-/-+FA组小鼠肾小管间质胶原相比WT+FA组明显增多，显示Manba-/-小鼠在叶酸作用后较WT组小鼠出现更严重的肾脏纤维化(图3)。
3.结论
以上结果显示，敲除Manba基因能够加重小鼠由叶酸诱导所致的肾纤维化，提示Manba为肾纤维化的靶基因，在抑制肾纤维化疾病的进程中起着十分重要的作用。该Manba基因敲除小鼠肾纤维化模型具有良好的前景和临床意义，可应用于开发治疗和/或预防肾纤维化的药物。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (12)
1.一种Manba基因敲除的动物肾纤维化模型的构建方法，其特征在于，包括如下步骤：
1)杂交得到Manba基因敲除的纯合子动物；
2)向Manba基因敲除的纯合子动物注射有效量的叶酸；
3)获得Manba基因敲除的动物肾纤维化模型。
2.如权利要求1所述的构建方法，其特征在于，所述动物为小鼠。
3.如权利要求1所述的构建方法，其特征在于：步骤2)所述注射为腹腔注射。
4.如权利要求2所述的构建方法，其特征在于：步骤2)中所述叶酸的注射剂量为200-300μg/g体重。
5.如权利要求4所述的构建方法，其特征在于：所述叶酸的注射剂量为250μg/g体重。
6.如权利要求1-5任一所述的构建方法，其特征在于：所述叶酸溶于碱性缓冲液后，再注射到动物体内。
7.如权利要求6所述的构建方法，其特征在于：所述碱性缓冲液是NaHCO3溶液。
8.如权利要求7所述的构建方法，其特征在于：所述NaHCO3溶液中NaHCO3和水的重量比是1：40。
9.Manba基因纯合敲除在构建肾纤维化动物模型中的用途。
10.一种由权利要求1-8任一所述的构建方法构建的Manba基因敲除的动物肾纤维化模型。
11.权利要求10所述的Manba基因敲除的动物肾纤维化模型在制备或筛选治疗和/或预防肾纤维化的药物中的用途。
12.一种筛选治疗和/或预防肾纤维化的药物的方法，其特征在于：所述方法包括以下步骤：
1)由权利要求1-8任一所述的构建方法构建获得Manba基因敲除的动物肾纤维化模型；
2)利用步骤1)制备得到的动物模型筛选对肾纤维化具有治疗和/或预防效果的药物。
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