10-HDA对急性氯化镉所致肾损伤的保护作用及自噬相关蛋白表达的影响
Protective effect of 10-HDA on acute cadmium chloride-induced kidney damage and autophagy protein expression
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摘要:
背景 急性镉暴露会引起多种组织器官损伤，肾脏是主要靶器官。镉诱导的急性肾损伤涉及多个复杂的机制，其中氧化应激和自噬起着重要作用。
目的 探讨10-羟基-2-癸烯酸（10-HDA）对氯化镉染毒小鼠急性肾损伤的影响，为镉中毒的发病机制和防治提供实验依据。
方法 将35只雄性C57BL/6小鼠按体重随机分为7组，每组5只。对照组腹腔注射生理盐水，染镉组腹腔注射4 mg·kg−1氯化镉溶液，干预组腹腔注射4 mg·kg−1氯化镉溶液同时灌胃50、100、150、200 mg·kg−1的10-HDA，10-HDA组仅予以150 mg·kg−1的10-HDA灌胃处理；连续处理14 d。最后一次染毒结束24 h后，通过检测血尿素氮、肌酐、丙二醛（MDA）、超氧化物歧化酶（SOD）等生理学指标，病理学指标，自噬相关蛋白（Atg7、Atg5、Beclin-1、LC3）和线粒体自噬相关蛋白（PINK1、Parkin）表达情况，检测10-HDA对氯化镉暴露所致肾损伤的作用。
结果 与对照组比较，染镉组小鼠体重明显降低（
P <0.01）；不同浓度的10-HDA干预后，小鼠体重较染镉组明显增长（P <0.01）。染镉组小鼠血尿素氮和肌酐水平均高于对照组（P <0.01）；100、150、200 mg·kg−1 10-HDA干预后小鼠血尿素氮和肌酐含量较染镉组均有不同程度减少（P <0.01）。染镉组小鼠肾皮质MDA水平高于对照组，SOD活性低于对照组（P <0.01）；不同剂量10-HDA干预组小鼠肾皮质MDA含量较染镉组有不同程度降低，SOD活性有不同程度增加（P <0.01），肾脏结构发生病理改变。氯化镉组Atg7、LC3-II/I表达高于对照组（P <0.05），而Beclin-1的表达降低（P <0.05）；与氯化镉组相比，不同剂量10-HDA干预组的Atg7表达水平不同程度降减少，LC3-II/I表达在50、150、200 mg·kg−1 10-HDA干预组有不同程度减少，而Beclin-1的表达在50、100、150 mg·kg−1 10-HDA干预组增加（P <0.05）。染镉组和50 mg·kg−1 10-HDA干预组的PINK1和Parkin表达量低于对照组（P <0.01）；与氯化镉暴露组相比，在100、150、200 mg·kg−1 10-HDA干预后，PINK1表达量均有不同程度的增加，Parkin表达量在所有10-HDA干预组均有所增加（P <0.01）。结论 10-HDA处理可以减轻氯化镉引起的急性肾损伤，减少自噬相关蛋白的表达，增加线粒体自噬相关蛋白的表达。
Abstract:Background Acute cadmium (Cd) exposure can cause damage to multiple tissues, with the kidney being the primary target organ. The development of Cd-induced acute kidney injury involves complex mechanisms, in which autophagy and oxidative stress play crucial roles.
Objective To investigate the effect of 10-hydroxy-2-decenoic acid (10-HDA) on kidney injury in mice exposed to cadmium, and provide experimental basis for studying the pathogenesis and prevention of Cd poisoning.
Methods Thirty-five male C57BL/6 mice were divided into 7 groups (each of 5 mice): control group (normal saline, intraperitoneal injection), CdCl2 group (4 mg·kg−1, intraperitoneal injection), intervention groups ( 4 mg·kg−1 CdCl2, intraperitoneal Injection + 50, 100, 150, or 200 mg·kg−1 10-HDA, oral gavage), and 10-HDA group (150 mg·kg−1, oral gavage). All treatments were given for 14 d. Twenty-four hours after the last infection, physiological indicators blood urea nitrogen (BUN), creatinine (CRE), malondialdehyde (MDA), and superoxide dismutase (SOD), histopathological indicators, autophagy-related proteins (Atg7, Atg5, Beclin-1, and LC3), and mitochondrial autophagy-related proteins (PINK1 and Parkin) were detected to examine the effect of 10-HDA on kidney injury caused by CdCl2.
Results Compared with the control group, the body weight of mice in the CdCl2 group was significantly reduced (
P <0.01); compared with the CdCl2 group, the body weight of mice after intervention with different concentrations of 10-HDA was significantly increased (P <0.01). CdCl2 significantly increased BUN and CRE in the serum samples compared with the control group (P <0.01), which was significantly reduced to varying degrees after 100, 150, and 200 mg·kg−1 10-HDA intervention (P <0.01). MDA significantly increased and SOD significantly decreased in the renal cortex following CdCl2 administration compared with the control group (P <0.01), which was resolved following 10-HDA administration at different concentrations (P <0.01). In histopathological studies, 10-HDA restored injured kidney tissues induced by CdCl2. The expression levels of autophagy proteins Atg7 and LC3-II/I were significantly increased (P <0.05), and the expression level of Beclin-1 was significantly decreased (P <0.05) in the CdCl2 group compared with the control group. The expression levels of Atg7 were reduced to varying degrees after treatment with designed concentrations of 10-HDA, the expression levels of LC3-II/I were also reduced in the 50, 150, and 200 mg·kg−1 10-HDA intervention groups, and the expression levels of Beclin-1 were increased in the 50, 100, and 150 mg·kg−1 10-HDA intervention groups (P <0.05). The expression levels of PINK1 and Parkin in the CdCl2 group and the 50 mg·kg−1 10-HDA intervention group were lower than those in the control group (P <0.01). Compared with the CdCl2 group, the expression levels of PINK1 increased to varying degrees after 100, 150, and 200 mg·kg−1 10-HDA intervention, and the expression levels of Parkin increased in all 10-HDA intervention groups (P <0.01).Conclusion The intervention using 10-HDA can lessen acute kidney injury caused by CdCl2, reduce the expression of autophagy-related proteins, and increase the expression of mitochondrial autophagy-related proteins.
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