CN116999556A - Cdc42作为AKI的防治靶标及其抑制剂作为AKI防治药物的应用 - Google Patents
Cdc42作为AKI的防治靶标及其抑制剂作为AKI防治药物的应用 Download PDFInfo
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Abstract
本发明公开了Cdc42作为AKI的防治靶标及其抑制剂作为AKI防治药物的应用,解决了现有技术中临床上缺乏有效防治AKI的药物和方法的问题。通过靶向Cdc42可以显著降低AKI小鼠尿素、肌酐水平的升高,并且Cdc42抑制剂对AKI小鼠具有预防和治疗作用。Cdc42可作为AKI的治疗靶标,Cdc42抑制剂可作为AKI的有效治疗药物。本发明对AKI发病机制的探索以及有效治疗药物的寻求具有重要的意义。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及Cdc42作为AKI的防治靶标及其抑制剂作为AKI防治药物的应用。
背景技术
急性肾损伤(AKI)是以肾功能短时间内的急速下降为特征,具有高发病率、高死亡率且预后不佳的临床常见疾病,AKI在重症监护室病人中的死亡率高达50%以上,是住院病人死亡的独立危险因素。
细胞分裂周期42(Cdc42)属于Rho GTPases家族成员之一,是肌动蛋白细胞骨架动力学的主要调节因子。Cdc42通过调节肌动蛋白细胞骨架的可塑性,参与细胞形状、运动、迁移、细胞周期、囊泡运输等多进程,其广泛的生物学功能使其在多种疾病中发挥重要作用。
AKI已成为世界性的全球公共卫生问题,为社会和患者都带来严重的负担。由于肾功能的急速丧失,致使体内含氮物质(肌酐、尿素)的大量积累,即使是轻微的、可逆的AKI也会产生严重的临床后果,增加死亡风险。目前AKI的病理生理学尚未得到充分的阐明,其发病机制尚不明确,临床上缺乏可治疗AKI的药物和方法。因此探索AKI潜在的发病机制以及寻找有效的治疗药物对于AKI患者的生存及预后至关重要。
发明内容
本发明的目的在于提供Cdc42作为AKI的防治靶标及其抑制剂作为AKI防治药物的应用,以解决现有技术中的临床上缺乏可治疗AKI的药物和方法的问题。
为实现上述目的,本发明提供了以下技术方案:
本发明提供的Cdc42作为AKI的防治靶标,在筛选或开发肾功能在短时间内的急速下降为特征的疾病防治药物中的应用。
进一步的,所述疾病为急性肾损伤。
Cdc42抑制剂在制备AKI防治药物产品中的应用。
进一步的,所述产品用于治疗急性肾损伤以及肾功能在短时间内的急速下降为特征的疾病。
进一步的,所述产品通过降低尿素、肌酐水平的上升对AKI进行预防和治疗。
进一步的,所述Cdc42抑制剂包括ZCL278,具体结构如下:
基于上述技术方案,本发明至少可以产生如下技术效果:
通过靶向Cdc42可以减少AKI小鼠尿素、肌酐水平的升高,Cdc42抑制剂对AKI小鼠具有预防和治疗作用,Cdc42可作为AKI的治疗靶标,Cdc42抑制剂可作为AKI的有效治疗药物。本发明对AKI发病机制的探索以及有效治疗药物的寻求具有重要的意义。
附图说明
为了更清楚地说明本发明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,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图示出的结构获得其他的附图。
图1为本发明实施例1Cdc42在对照小鼠、AKI小鼠、和AKI经Cdc42抑制剂处理小鼠肾脏组织的蛋白表达情况;
图2为本发明实施例1各组小鼠血液尿素、肌酐水平变化;
图3为本发明实施例1肾小管上皮细胞特异性Cdc42敲低小鼠及其同窝对照小鼠肾脏组织的蛋白表达情况;
图4为本发明实施例1肾小管上皮细胞特异性Cdc42敲低显著降低AKI小鼠血液尿素、肌酐水平。
具体实施方式
应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明。
为使本发明的目的、技术方案和优点更加清楚,下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
1、检测Cdc42在AKI小鼠肾脏表达以及Cdc42抑制剂ZCL278对AKI的预防及治疗效果
1.1选择8-10周,体重20-25g左右的C57BL/6雄性小鼠,AKI模型组小鼠腹腔注射20mg/kg剂量的顺铂,对照组小鼠注射等体积的生理盐水。
1.2顺铂注射前24h给小鼠腹腔注射ZCL278(30mg/kg)进行预处理,顺铂注射后24h和48h各注射一次ZCL278(30mg/kg),对照组注射等体积的溶剂和生理盐水,顺铂注射72h后处死小鼠,收集血液用于尿素、肌酐水平的检测来探索ZCL278对AKI的预防及治疗效果。
1.3顺铂注射后24h和48h各注射一次ZCL278(30mg/kg),对照组注射等体积的溶剂和生理盐水。顺铂注射72h后处死小鼠,收集血液用于尿素、肌酐水平的检测来探索ZCL278对AKI的治疗效果(结果见附图2)
1.4检测对照小鼠、AKI小鼠、以及用ZCL278处理的AKI小鼠的肾脏组织Cdc42蛋白水平的表达变化(结果见附图1)。
2、靶向Cdc42可缓解小鼠AKI,其抑制剂ZCL278对AKI小鼠具有预防和治疗作用
顺铂给药72h小时后,通过液质联用法检测小鼠血液尿素和肌酐水平的变化。如附图2所示,实验结果发现抑制Cdc42可显著降低尿素、肌酐水平的上升,其抑制剂ZCL278对AKI小鼠具有预防和治疗作用。说明Cdc42参与了AKI的发病机制,可作为AKI的潜在治疗靶标,抑制剂ZCL278可作为AKI的有效治疗药物。
3、肾小管上皮细胞特异性敲低Cdc42可降低AKI小鼠尿素、肌酐水平的升高
特异性敲低小鼠肾小管上皮细胞中的Cdc42(附图3),顺铂给药72h小时后处死小鼠。收集Cdc42肾小管上皮细胞特异性敲低鼠(CKO)及其对照组(WT)小鼠的血液,通过液质联用法检测小鼠血液尿素和肌酐水平的变化。如图附4所示,实验结果发现顺铂给药后,CKO组小鼠尿素和肌酐水平显著低于WT组小鼠,说明Cdc42可作为AKI的潜在治疗靶标。
最后应说明的是:
以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (5)
1. Cdc42作为AKI的防治靶标,在筛选或开发肾功能在短时间内的急速下降为特征的疾病防治药物中的应用。
2.根据权利要求1所述的Cdc42作为AKI的防治靶标,其特征在于,所述疾病为急性肾损伤。
3. Cdc42抑制剂在制备AKI防治药物产品中的应用,所述Cdc42抑制剂包括ZCL278。
4.根据权利要求3所述的Cdc42抑制剂在制备AKI防治药物产品中的应用,其特征在于,所述产品用于治疗急性肾损伤以及肾功能在短时间内的急速下降为特征的疾病。
5.根据权利要求3所述的Cdc42抑制剂在制备AKI防治药物产品中的应用,其特征在于,所述产品通过降低尿素、肌酐水平的上升对AKI进行预防和治疗。
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