基于UHPLC-QE-MS的高原鼠兔肾脏差异代谢物及低氧适应机制分析

doi:10.12300/j.issn.1674-5817.2024.095

实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (1): 3-12.DOI: 10.12300/j.issn.1674-5817.2024.095

• 实验动物资源开发与利用 • 上一篇下一篇

基于UHPLC-QE-MS的高原鼠兔肾脏差异代谢物及低氧适应机制分析

何雨昕¹()(), 白振忠¹^,², 薛华¹, 郭子旭¹, 曹学锋¹^,²()()

^1.青海大学医学院, 西宁 810001
^2.青海大学高原医学研究中心, 西宁 810001

收稿日期:2024-07-10 修回日期:2024-12-11 出版日期:2025-03-12 发布日期:2025-02-25
通讯作者: 曹学锋（1977—），男，博士，副教授，硕士生导师，研究方向：慢性高原病及低氧适应机制与损伤干预。E-mail： 2002980001@qhu.edu.cn。ORCID：0000-0002-0612-4616
作者简介:何雨昕（1999—），女，硕士研究生，研究方向：慢性高原病及低氧适应机制与损伤干预。E-mail： 2650279239@qq.com。ORCID：0009-0004-5385-8905
曹学锋，医学博士，副教授，硕士研究生导师。现任职于青海大学医学院基础医学部，曾赴美国犹他大学人类分子遗传实验中心做访问学者，主要从事病理生理学及相关学科的教学与科研工作。主要研究方向为高原病与高原低氧适应机制及损伤干预，擅长从代谢、线粒体能量利用、高原病药物干预等角度，研究高原低氧下高原世居人群和土著动物适应极端环境的分子生物学机制以及损伤干预机制。2019年参与项目“青藏高原多民族地区医学机能实验平台搭建及实验教学改革与创新实践研究”荣获国家教学成果二等奖；2022年获得青海省“高端创新人才”培养拔尖人才项目；2023年作为主要完成人参与的“高原鼠兔氧传递及细胞呼吸特征和白色脂肪棕色化机制”研究荣获青海省科学技术成果奖。近年来主持“藏药莪达夏干预低氧性肺动脉高压中的G6PD蛋白修饰组学研究”等国家级、省部级科研课题4项，参编《高原临床病理生理学》等国家规划教材3部，以第一作者身份发表SCI论文、国内核心期刊论文16篇。E-mail： 2002980001@qhu.edu.cn。ORCID：0000-0002-0612-4616
基金资助:
青海省昆仑英才·高端创新人才·培养领军项目(K9924072)

Analysis of Kidney Differential Metabolites and Hypoxia Adaptation Mechanism of Plateau Pikas Based on UHPLC-QE-MS

HE Yuxin¹()(), BAI Zhenzhong¹^,², XUE Hua¹, GUO Zixu¹, CAO Xuefeng¹^,²()()

^1.Medical College of Qinghai University, Xining 810001, China
^2.High Altitude Medical Research Center, Qinghai University, Xining 810001, China

Received:2024-07-10 Revised:2024-12-11 Published:2025-02-25 Online:2025-03-12
Contact: CAO Xuefeng (ORCID: 0000-0002-0612-4616), E-mail: 2002980001@qhu.edu.cn

摘要/Abstract

摘要：

目的运用超高效液相色谱-四极杆静电场轨道阱质谱（ultra-high-performance liquid chromatography coupled with quadrupole electrostatic field orbital trap-mass spectrometry，UHPLC-QE-MS）非靶向代谢组学分析法探讨不同海拔高原鼠兔肾脏低氧适应性代谢变化的潜在机制。方法捕捉青海省果洛藏族自治州玛多县星宿海地区海拔4 360 m（MD组）和青海省海北藏族自治州门源地区海拔2 900 m（MY组）处的高原鼠兔各10只，经麻醉后采集血清样本，经安死术后采集肾脏样本，分别进行一般生理生化指标测定和代谢组学分析。其中一部分血清样本用于血液学分析，另一部分用于血气分析，剩余部分检测生化指标。肾组织样本中代谢物提取后，进行UHPLC-QE-MS分析，运用代谢组学主成分分析（principal component analysis，PCA）和正交偏最小二乘判别分析（orthogonal partial least squares discriminant analysis，OPLS-DA）方法分析差异代谢物，筛选标准为变量投影重要度（variable Importance in the projection，VIP）>1.5且倍数变化（fold change，FC）>1.5或VIP>1.5且FC<1/1.5。利用相关性分析热力图、差异显著性分析火山图、信号通路识别气泡图和矩形图分别分析差异代谢物及相关信号通路。结果 MD组高原鼠兔的红细胞计数、葡萄糖、尿素氮、尿酸和同型半胱氨酸含量高于MY组，而血红蛋白、血细胞比容、肌酐和二氧化碳结合力低于MY组，这表明不同海拔的高原鼠兔血液携氧能力存在明显差异。经主成分模式识别分析和OPLS-DA置换检验显示，MD组和MY组高原鼠兔肾脏代谢物具有明显的聚类型分布（R2Y=0.930，Q2=0.655）。按照筛选标准，并经数据库比对发现，不同海拔高原鼠兔的肾脏代谢物差异分子有46个，其中MD组高原鼠兔的蟾蜍二烯羟酸内酯、腺苷、腺嘌呤、薯蓣皂苷、盐酸小檗碱、鼠尾草酚和虾青素表达水平均显著升高（VIP＞1.5，P＜0. 05），花生四烯酸、组胺和香豆素水平显著下降（VIP＞1.5，P＜0.05）。相关信号通路分析显示，缬氨酸、亮氨酸和异亮氨酸生物合成通路具有最大影响因子（P＜0.05），而泛酸盐和辅酶A生物合成通路呈现最显著富集（P＜0.05）。结论不同海拔高原鼠兔肾脏差异代谢物氨基酸、泛酸盐及辅酶A通路可能参与高原鼠兔高原低氧适应代谢机制。

关键词: 高原低氧, 高原鼠兔, 肾脏, 超高效液相色谱-四极杆静电场轨道阱质谱, 代谢通路

Abstract:

Objective To explore the potential mechanisms of hypoxic adaptive metabolic changes in the kidneys of plateau pikas at different altitudes using non-targeted metabolomics analysis via ultra-high-performance liquid chromatography coupled with quadrupole electrostatic field orbital trap-mass spectrometry (UHPLC-QE-MS). Methods 10 plateau pikas were captured at an altitude of 4 360 m in Xingxiuhai area, Maduo County, Guoluo Tibetan Autonomous Prefecture, Qinghai Province (MD group), and 10 plateau pikas were captured at an altitude of 2 900 m in Menyuan area, Haibei Tibetan Autonomous Prefecture, Qinghai Province (MY group). After anesthesia, serum samples were collected, and kidney samples were collected after euthanasia. General physiological and biochemical indicators were measured and metabolomics analysis was performed. Part of the serum samples was used for hematology analysis, another part for blood gas analysis, and the remaining part for biochemical indicator detection. Metabolites were extracted from the kidney tissue samples and then analyzed using UHPLC-QE-MS. Differential metabolites were analyzed using metabolomics principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), with screening criteria set as variable importance in projection (VIP)>1.5 and fold change (FC)>1.5, or VIP>1.5 and FC<1/1.5. Correlation analysis heatmaps, significance analysis volcano plots, signaling pathway recognition bubble charts, and rectangular graphs were used for the analysis of differential metabolites and related signaling pathways. Results The red blood cell count, glucose, urea nitrogen, uric acid, and homocysteine levels in the MD group plateau pikas were higher than those in the MY group, while hemoglobin, hematocrit, creatinine, and carbon dioxide combining power were lower than those in the MY group. This indicated a significant difference in the blood oxygen-carrying capacity of plateau pikas at different altitudes. The principal component pattern recognition analyses, and OPLS-DA permutation test showed that the kidney metabolites of the MD and MY groups of plateau pikas had distinct clustering distributions (R2Y=0.930, Q2=0.655). According to the screening criteria and database comparison, 46 differential metabolites were identified in the kidneys of plateau pikas at different altitudes. In the MD group of plateau pikas, the expression levels of bufadienolide, adenosine, adenine, diosgenin, berberine chloride, carnosol, and astaxanthin were significantly increased (VIP>1.5, P<0.05), while the levels of arachidonic acid, histamine, and coumarin were significantly decreased (VIP>1.5, P<0.05). The analysis of related signaling pathways showed that the biosynthetic pathways of valine, leucine, and isoleucine had the largest impact factors (P<0.05), while the biosynthetic pathways of pantothenate and coenzyme A showed the most significant enrichment (P<0.05). Conclusion The differential metabolites of amino acids, pantothenate, and coenzyme A pathways in the kidneys of plateau pikas at different altitudes may be involved in the metabolic mechanisms of plateau pikas' hypoxia adaptation in high-altitude environments.

Key words: High-altitude hypoxia, Plateau pika, Kidney, UHPLC-QE-MS, Metabolic pathway

中图分类号:

Q95-33

何雨昕,白振忠,薛华,等. 基于UHPLC-QE-MS的高原鼠兔肾脏差异代谢物及低氧适应机制分析[J]. 实验动物与比较医学, 2025, 45(1): 3-12. DOI: 10.12300/j.issn.1674-5817.2024.095.

HE Yuxin,BAI Zhenzhong,XUE Hua,et al. Analysis of Kidney Differential Metabolites and Hypoxia Adaptation Mechanism of Plateau Pikas Based on UHPLC-QE-MS[J]. Laboratory Animal and Comparative Medicine, 2025, 45(1): 3-12. DOI: 10.12300/j.issn.1674-5817.2024.095.

图/表 4

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项目 Item	MD组 MD group (n=10)	MY组 MY group (n=10)	t值 t value	P 值 P value
RBC C_cell/(10¹²·L^-1)	6.93±0.85	6.75±1.65	0.355	0.726
HGB ρ/(g·L^-1)	116.36±7.39	141.40±21.45	-4.074	0.001
HCT φ/(%)	36.45±2.62	42.58±7.09	-2.985	0.007
GLU c/(mmol·L^-1)	6.07±3.66	5.84±2.51	0.177	0.861
BUN c/(mmol·L^-1)	7.48±4.01	5.89±3.00	1.054	0.305
Cr c/(µmol·L^-1)	21.55±5.97	22.36±8.65	-0.258	0.799
UA c/(µmol·L^-1)	45.09±21.90	24.27±15.84	2.555	0.019
CO₂CP c/(mmol·L^-1)	18.72±5.85	26.01±5.83	-2.928	0.008
HCY c/(µmol·L^-1)	25.03±10.31	18.35±12.09	1.393	0.179

项目 Item	MD组 MD group (n=10)	MY组 MY group (n=10)	t值 t value	P 值 P value
RBC C_cell/(10¹²·L^-1)	6.93±0.85	6.75±1.65	0.355	0.726
HGB ρ/(g·L^-1)	116.36±7.39	141.40±21.45	-4.074	0.001
HCT φ/(%)	36.45±2.62	42.58±7.09	-2.985	0.007
GLU c/(mmol·L^-1)	6.07±3.66	5.84±2.51	0.177	0.861
BUN c/(mmol·L^-1)	7.48±4.01	5.89±3.00	1.054	0.305
Cr c/(µmol·L^-1)	21.55±5.97	22.36±8.65	-0.258	0.799
UA c/(µmol·L^-1)	45.09±21.90	24.27±15.84	2.555	0.019
CO₂CP c/(mmol·L^-1)	18.72±5.85	26.01±5.83	-2.928	0.008
HCY c/(µmol·L^-1)	25.03±10.31	18.35±12.09	1.393	0.179

峰值 Peak	代谢物 Metabolites		MD组vs MY组 MD group vs MY group
峰值 Peak	中文名 Chinese name	英文名 English name	RT/s	VIP	P value	FC
4217	蟾蜍二烯羟酸内酯	Bufadienolide	302.521	2.841	0.046 1	216.417
3586	薯蓣皂苷配基	Diosgenin	375.853	2.790	0.000 0	23.644
2596	盐酸小檗碱	Berberine chloride	448.647	1.684	0.010 1	2.418
5668	顺丁烯二酰亚胺	Maleimide	157.759	2.051	0.003 3	2.275
6118	腺嘌呤	Adenine	128.009	1.992	0.002 6	1.355
4040	7,8-脱氢虾青素	7,8-Dehydroastaxanthin	304.975	2.124	0.007 8	13.719
4168	贝那普利酯	Benazeprilat	279.705	2.212	0.000 8	10.772
4196	胆固醇-3,7,12,25-呋喃-3-葡萄糖醛酸	Cholestane-3,7,12,25-tetrol-3-glucuronide	273.513	2.149	0.001 2	5.633
4221	7-乙氧基香豆素	7-Ethoxycoumarin	261.173	1.795	0.017 9	2.839
3212	1-硬脂酰甘油磷酸甘油	1-Stearoylglycerophosphoglycerol	412.530	1.586	0.025 1	2.103
5578	2-甲氧基对乙酰氨基酚硫酸盐	2-Methoxyacetaminophen sulfate	36.282	2.150	0.000 5	0.453
5294	黄嘌呤	Xanthosine	57.261	1.863	0.007 7	0.448
5476	四氢生物蝶呤	Tetrahydrobiopterin	42.319	1.632	0.011 0	0.425
2896	小穗苎麻素	Cryptopleurine	440.968	2.258	0.000 3	0.292
3198	坎二酸	Canbidiolic acid	413.844	2.004	0.012 7	0.284
5570	GDP-3,6-二脱氧-D-半乳糖	GDP-3,6-dideoxy-D-galactose	36.317	1.735	0.001 6	0.197
5501	棉酚	Gossypol	41.544	1.725	0.019 3	0.160
4549	4-香豆素基莽草酸酯	4-Coumaroylshikimate	179.435	2.266	0.009 7	0.103
4596	紫丁香苷	Syringin	169.451	2.374	0.010 3	0.050
5805	5-O-甲基-间氨基-肌醇	5-O-Methyl-myo-inositol	33.358	2.543	0.000 5	0.026
5001	癸二酸	Sebacic acid	135.122	2.295	0.046 3	0.077
4671	萨马素A	Samaderin A	163.209	1.535	0.037 8	0.217
4717	3-脱氢酶	3-Dehydrogenase	157.505	2.158	0.000 9	0.170
4514	硫烯草丹	Sulfallate	185.215	1.844	0.049 0	0.190
5688	双甲苯苄醇	Bitolterol	35.519	1.568	0.001 1	0.271
5523	烟碱	Nicotiamine	169.858	2.201	0.000 1	0.454
7265	吡达隆	Pyridarone	29.322	1.490	0.019 5	0.401
3058	高肌肽	Homocarnosine	412.238	1.966	0.006 3	0.390
3410	阿非迪霉素	Aphidicolin	388.298	2.133	0.005 0	0.205
3101	松香酸盐	Abietate	408.903	2.373	0.033 4	0.088
4573	秦皮苷	Fraxin	174.802	1.098	0.034 3	0.085
3554	高多环内酯	Homodolicholide	380.038	1.667	0.004 0	0.234
3984	法尼基半胱氨酸	Farnesylcysteine	328.343	2.148	0.015 9	0.224
59	泛酸	Pantothenic acid	157.754	2.460	0.000 1	0.480
6640	1-甲基腺苷	1-Methyladenosine	44.286	2.135	0.003 3	0.482
5674	L-二氢脱壳素	L-Dihydroanticapsin	157.754	2.510	0.000 1	0.463
3695	十八碳四烯酸	Stearidonic acid	359.953	2.698	0.003 7	0.103
4631	6-脱氧巴西红厚壳素	6-Deoxyjacareubin	237.103	2.310	0.011 0	0.096
5940	异戊烯焦磷酸	Isopentenyl diphosphate	142.170	2.771	0.038 3	0.004
6407	环氧化物青蒿琥酯	Artomunoxanthentrione epoxide	27.729	2.401	0.000 0	0.249
5768	苄基青霉酸	Benzylpenicilloic acid	151.870	2.655	0.025 4	0.034
302	异亮氨酸	Isoleucine	71.954	1.669	0.045 9	0.698
6496	L-缬氨酸	L-Valine	55.803	1.684	0.018 2	0.637
4165	鼠尾草酚	Carnosol	279.762	2.070	0.003 8	31.391
41	花生四烯酸	Arachidonic acid	466.526	1.614	0.010 5	0.695
5711	组胺	Histamine	35.217	1.740	0.042 9	0.537

峰值 Peak	代谢物 Metabolites		MD组vs MY组 MD group vs MY group
峰值 Peak	中文名 Chinese name	英文名 English name	RT/s	VIP	P value	FC
4217	蟾蜍二烯羟酸内酯	Bufadienolide	302.521	2.841	0.046 1	216.417
3586	薯蓣皂苷配基	Diosgenin	375.853	2.790	0.000 0	23.644
2596	盐酸小檗碱	Berberine chloride	448.647	1.684	0.010 1	2.418
5668	顺丁烯二酰亚胺	Maleimide	157.759	2.051	0.003 3	2.275
6118	腺嘌呤	Adenine	128.009	1.992	0.002 6	1.355
4040	7,8-脱氢虾青素	7,8-Dehydroastaxanthin	304.975	2.124	0.007 8	13.719
4168	贝那普利酯	Benazeprilat	279.705	2.212	0.000 8	10.772
4196	胆固醇-3,7,12,25-呋喃-3-葡萄糖醛酸	Cholestane-3,7,12,25-tetrol-3-glucuronide	273.513	2.149	0.001 2	5.633
4221	7-乙氧基香豆素	7-Ethoxycoumarin	261.173	1.795	0.017 9	2.839
3212	1-硬脂酰甘油磷酸甘油	1-Stearoylglycerophosphoglycerol	412.530	1.586	0.025 1	2.103
5578	2-甲氧基对乙酰氨基酚硫酸盐	2-Methoxyacetaminophen sulfate	36.282	2.150	0.000 5	0.453
5294	黄嘌呤	Xanthosine	57.261	1.863	0.007 7	0.448
5476	四氢生物蝶呤	Tetrahydrobiopterin	42.319	1.632	0.011 0	0.425
2896	小穗苎麻素	Cryptopleurine	440.968	2.258	0.000 3	0.292
3198	坎二酸	Canbidiolic acid	413.844	2.004	0.012 7	0.284
5570	GDP-3,6-二脱氧-D-半乳糖	GDP-3,6-dideoxy-D-galactose	36.317	1.735	0.001 6	0.197
5501	棉酚	Gossypol	41.544	1.725	0.019 3	0.160
4549	4-香豆素基莽草酸酯	4-Coumaroylshikimate	179.435	2.266	0.009 7	0.103
4596	紫丁香苷	Syringin	169.451	2.374	0.010 3	0.050
5805	5-O-甲基-间氨基-肌醇	5-O-Methyl-myo-inositol	33.358	2.543	0.000 5	0.026
5001	癸二酸	Sebacic acid	135.122	2.295	0.046 3	0.077
4671	萨马素A	Samaderin A	163.209	1.535	0.037 8	0.217
4717	3-脱氢酶	3-Dehydrogenase	157.505	2.158	0.000 9	0.170
4514	硫烯草丹	Sulfallate	185.215	1.844	0.049 0	0.190
5688	双甲苯苄醇	Bitolterol	35.519	1.568	0.001 1	0.271
5523	烟碱	Nicotiamine	169.858	2.201	0.000 1	0.454
7265	吡达隆	Pyridarone	29.322	1.490	0.019 5	0.401
3058	高肌肽	Homocarnosine	412.238	1.966	0.006 3	0.390
3410	阿非迪霉素	Aphidicolin	388.298	2.133	0.005 0	0.205
3101	松香酸盐	Abietate	408.903	2.373	0.033 4	0.088
4573	秦皮苷	Fraxin	174.802	1.098	0.034 3	0.085
3554	高多环内酯	Homodolicholide	380.038	1.667	0.004 0	0.234
3984	法尼基半胱氨酸	Farnesylcysteine	328.343	2.148	0.015 9	0.224
59	泛酸	Pantothenic acid	157.754	2.460	0.000 1	0.480
6640	1-甲基腺苷	1-Methyladenosine	44.286	2.135	0.003 3	0.482
5674	L-二氢脱壳素	L-Dihydroanticapsin	157.754	2.510	0.000 1	0.463
3695	十八碳四烯酸	Stearidonic acid	359.953	2.698	0.003 7	0.103
4631	6-脱氧巴西红厚壳素	6-Deoxyjacareubin	237.103	2.310	0.011 0	0.096
5940	异戊烯焦磷酸	Isopentenyl diphosphate	142.170	2.771	0.038 3	0.004
6407	环氧化物青蒿琥酯	Artomunoxanthentrione epoxide	27.729	2.401	0.000 0	0.249
5768	苄基青霉酸	Benzylpenicilloic acid	151.870	2.655	0.025 4	0.034
302	异亮氨酸	Isoleucine	71.954	1.669	0.045 9	0.698
6496	L-缬氨酸	L-Valine	55.803	1.684	0.018 2	0.637
4165	鼠尾草酚	Carnosol	279.762	2.070	0.003 8	31.391
41	花生四烯酸	Arachidonic acid	466.526	1.614	0.010 5	0.695
5711	组胺	Histamine	35.217	1.740	0.042 9	0.537

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基于UHPLC-QE-MS的高原鼠兔肾脏差异代谢物及低氧适应机制分析

Analysis of Kidney Differential Metabolites and Hypoxia Adaptation Mechanism of Plateau Pikas Based on UHPLC-QE-MS

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