钼、镉联合暴露介导氧化应激和铁死亡致绵羊肾损伤

doi:10.11843/j.issn.0366-6964.2024.12.042

畜牧兽医学报 ›› 2024, Vol. 55 ›› Issue (12): 5802-5812.doi: 10.11843/j.issn.0366-6964.2024.12.042

钼、镉联合暴露介导氧化应激和铁死亡致绵羊肾损伤

熊志伟¹^,²(), 王云², 曹华斌¹, 彭成诚³, 杨帆¹, 代雪艳¹, 幸程鸿¹, 刘灵莉¹, 李静妮¹, 胡爱明⁴^,*()

1. 江西农业大学动物科学技术学院江西省畜禽疫病诊断与防控重点实验室，南昌 330045
2. 江西生物科技职业学院，南昌 330100
3. 广西科技大学医学部药学系，柳州 545005
4. 吉安市农业农村产业发展服务中心，吉安 343000

收稿日期:2024-01-02 出版日期:2024-12-23 发布日期:2024-12-27
通讯作者: 胡爱明 E-mail:13698091664@163.com;15807969386@163.com
作者简介:熊志伟(1997-)，男，江西南昌人，博士生，主要从事临床兽医学研究，E-mail：13698091664@163.com
基金资助:
江西省现代农业产业技术牛羊体系疫病防控岗(JXRS-13)

Molybdenum and Cadmium Combined Exposure Mediates Oxidative Stress and Ferroptosis Induced Kidney Damage in Sheep

XIONG Zhiwei¹^,²(), WANG Yun², CAO Huabin¹, PENG Chengcheng³, YANG Fan¹, DAI Xueyan¹, XING Chenghong¹, LIU Lingli¹, LI Jingni¹, HU Aiming⁴^,*()

1. Jiangxi Key Laboratory of Animal Disease Diagnosis and Control, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
2. Jiangxi Vocational College of Biotechnology, Nanchang 330100, China
3. Department of Pharmacy, Faculty of Medicine, Guangxi University of Science and Technology, Liuzhou 545005, China
4. Ji'an Agricultural and Rural Industry Development Service Center, Ji'an 343000, China

Received:2024-01-02 Online:2024-12-23 Published:2024-12-27
Contact: HU Aiming E-mail:13698091664@163.com;15807969386@163.com

摘要/Abstract

摘要：

旨在探究氧化应激及铁死亡在钼、镉及其联合暴露致绵羊肾组织损伤中的作用。以24只2月龄绵羊为试验对象，随机分为4组，即对照组(Control)、钼组(Mo)、镉组(Cd)和钼镉联合组(Mo+Cd)，对照组灌服等体积蒸馏水，Mo组灌服45 mg·kg^-1 BW的Mo，Cd组灌服1 mg·kg^-1 BW的Cd，Mo+Cd组灌服1 mg·kg^－1 BW Cd+45 mg·kg^-1 BW Mo。正试期为75 d。试验结束，取绵羊血清和肾组织，观察绵羊肾组织病理及超微病理学变化，并检测血清肾功能指标、肾组织氧化应激和铁死亡相关因子水平。结果显示，钼、镉及其联合暴露提高了血清肾功能指标(肌酐、尿素和尿酸)水平。Mo组、Cd组和Mo+Cd组中肾小管上皮细胞变性肿胀、结构模糊和溶解，在细胞质中有微小的红色颗粒和空泡，表现出颗粒变性、空泡变性和坏死。此外，肾小管管腔内有粉红色着染的丝缕样成分，部分肾小球及间质内红细胞数量增多。透射电镜结果显示，钼、镉及其联合暴露导致肾小管上皮细胞中线粒体体积变小且出现嵴模糊和空泡化。Mo组和Cd组中氧化损伤相关因子(H₂O₂、MDA)及Fe离子含量，铁死亡相关因子(NCOA4、ACSL4、TFR1和PTGS2)mRNA表达水平及PTGS2蛋白表达水平升高；抗氧化相关因子(GSH、CAT和GSH-Px)水平，铁死亡相关因子(SLC7A11、GPX4和FTH1)mRNA及蛋白表达水平降低，且上述变化在Mo+Cd组中更为明显。皮尔森相关性分析表明，氧化损伤相关因子(H₂O₂、MDA)和Fe离子水平与铁死亡相关因子(NCOA4、ACSL4、TFR1和PTGS2)表达水平呈正相关，与铁死亡相关因子(SLC7A11、GPX4和FTH1)表达水平呈负相关；抗氧化相关因子(GSH、CAT和GSH-Px)水平和铁死亡相关因子(NCOA4、ACSL4、TFR1和PTGS2)表达水平呈负相关，而与铁死亡相关因子(SLC7A11、GPX4和FTH1)表达水平呈正相关。本研究表明，钼镉及其联合暴露诱发绵羊肾氧化应激和铁死亡致肾组织损伤，且钼镉毒性具有协同效应。

关键词: 羊, 钼, 镉, 氧化应激, 铁死亡

Abstract:

The aim of this study was to investigate the role of oxidative stress and ferroptosis in renal tissue injury caused by molybdenum, cadmium and their combined exposure in sheep. Twenty-four sheep aged 2 months were randomly divided into 4 groups, namely control group (Control), molybdenum group (Mo), cadmium group (Cd) and molybdenum cadmium combined group (Mo+Cd). The control group was given equal volume of distilled water, the Mo group was given 45 mg Mo·kg^-1BW, group Cd was given 1 mg Cd·kg^-1BW, and group Mo+Cd was given 1 mg Cd+45 mg Mo·kg^-1BW. The experimental period lasted for 75 d. At the end of the experiment, serum and kidney tissue were collected, pathological and ultrapathological changes of sheep kidney were observed, and the levels of serum renal function indexes, renal tissue oxidative stress and ferroptosis related factors were detected. The results showed that molybdenum, cadmium and their combined exposure increased the levels of serum renal function indicators (creatinine, urea and uric acid). In the Mo, Cd, and Mo+Cd groups, the renal tubular epithelial cells underwent degeneration, manifesting as swelling, structural blurring, and lysis. The cytoplasm contained minute red granules and vacuoles, indicating granular degeneration, vacuolar degeneration, and necrosis. Additionally, the renal tubular lumens were observed to contain pink-stained filamentous components, while the number of red blood cells was elevated in some glomeruli and interstitial spaces. The results of transmission electron microscopy showed that molybdenum, cadmium and their combined exposure resulted in the reduction of mitochondrial volume, blurring of ridge and vacuolation in renal tubular epithelial cells. The contents of oxidative damage related factors (H₂O₂, MDA) and Fe ions, the mRNA expression levels of ferroptosis related factors (NCOA4, ACSL4, TFR1 and PTGS2) and the protein expression levels of PTGS2 were increased in Mo and Cd groups. The mRNA and protein expression levels of antioxidant related factors (GSH, CAT and GSH-Px) and ferroptosis related factors (SLC7A11, GPX4 and FTH1) were decreased, and the above changes were more obvious in Mo+Cd group. Pearson correlation analysis showed that the levels of oxidative damage related factors (H₂O₂, MDA) and Fe ions were positively correlated with the expression levels of ferroptosis related factors (NCOA4, ACSL4, TFR1 and PTGS2), and negatively correlated with the expression levels of ferroptosis related factors (SLC7A11, GPX4 and FTH1). The correlation of antioxidant related factors (GSH, CAT and GSH-Px) and ferroptosis related factors was opposite to that of oxidative damage related factors. This study shows that molybdenum cadmium and its combined exposure induced renal oxidative stress and ferroptosis in sheep, resulting in renal tissue damage, and molybdenum, cadmium toxicity has a synergistic effect.

Key words: sheep, molybdenum, cadmium, oxidative stress, ferroptosis

中图分类号:

S856.9

熊志伟, 王云, 曹华斌, 彭成诚, 杨帆, 代雪艳, 幸程鸿, 刘灵莉, 李静妮, 胡爱明. 钼、镉联合暴露介导氧化应激和铁死亡致绵羊肾损伤[J]. 畜牧兽医学报, 2024, 55(12): 5802-5812.

XIONG Zhiwei, WANG Yun, CAO Huabin, PENG Chengcheng, YANG Fan, DAI Xueyan, XING Chenghong, LIU Lingli, LI Jingni, HU Aiming. Molybdenum and Cadmium Combined Exposure Mediates Oxidative Stress and Ferroptosis Induced Kidney Damage in Sheep[J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(12): 5802-5812.

图/表 7

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基因 Gene	登录号 Accession number	上游引物(F)	下游引物(R)
NCOA4	XM_060406763.1	TTCAGAGCAGTCATTGCGGT	ACAATGGCAAACGTGGCATC
ACSL4	XM_042242179.1	CTCATGGGGTCGCAAAGAGT	GACAGTAGACGTTGGAAGTTGC
TFR1	XM_054347664.1	TCAGGTCAAAGGCAGTTCTCAA	TAGCATGGACCAGTTTGCCA
PTGS2	NM_001009432	CATGGGTGTGAAAGGGAGGAA	TCCCTTGGTGAAAGCTGGTC
SLC7A11	NM_001252182.1	GCAGGGCAGTGTTAATGGGAG	GCACGCCCTTAGGAGAGAT
GPX4	XM_060416444.1	GTTCGCTGCTGGCTATAACG	TCCATTTGATGGCGTTTCCC
FTH1	XM_060403847.1	TGACCGTGATGATGTGGCTTT	GCACAGCGCACATTCCATTG
GAPDH	XM_060411595.1	AGAGTGAGTGTCGCTGTTGAAGT	TCCGTTGTGGATCTGACCTG

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钼、镉联合暴露介导氧化应激和铁死亡致绵羊肾损伤

Molybdenum and Cadmium Combined Exposure Mediates Oxidative Stress and Ferroptosis Induced Kidney Damage in Sheep

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