钙敏感受体在高血压大鼠心肌重塑和视网膜血管病变中的作用研究

doi:10.12114/j.issn.1007-9572.2022.0520

中国全科医学 ›› 2023, Vol. 26 ›› Issue (05): 576-582.DOI: 10.12114/j.issn.1007-9572.2022.0520

所属专题：心血管最新文章合集；高血压最新文章合集

钙敏感受体在高血压大鼠心肌重塑和视网膜血管病变中的作用研究

赵佳琪¹, 刘薇¹, 唐娜¹, 王腊梅¹, 屈媛媛², 席冬梅¹, 钟华¹, 何芳¹^,^*()

1．832002　新疆维吾尔自治区石河子市，石河子大学医学院病理生理教研室　新疆地方病与民族病教育部重点实验室　国家卫生健康委中亚高发病防治重点实验室
2．832002　新疆维吾尔自治区石河子市，石河子大学医学院第一附属医院呼吸内科

收稿日期:2022-04-11 修回日期:2022-08-12 出版日期:2023-02-15 发布日期:2022-09-30
通讯作者: 何芳
作者贡献：赵佳琪提出研究选题方向，进行文章的构思与设计，负责数据收集和统计学分析；赵佳琪、刘薇、唐娜、王腊梅负责撰写论文和论文修订；刘薇、唐娜、屈媛媛、席冬梅负责数据收集、统计学分析、绘制图表；钟华、何芳进行数据复核，负责文章的质量控制及审校，对文章整体负责；所有作者确认了论文的最终稿。
基金资助:
国家自然科学基金资助项目(31960187); 中国医学科学院中央级公益性科研院所基本科研业务费专项资金资助项目(2020-PT330-003)

Role of Calcium-sensing Receptors in Myocardial Remodeling and Retinal Vasculopathy in Rat Models of Hypertension

ZHAO Jiaqi¹, LIU Wei¹, TANG Na¹, WANG Lamei¹, QU Yuanyuan², XI Dongmei¹, ZHONG Hua¹, HE Fang¹^,^*()

1. Department of Pathophysiology, School of Medicine, Shihezi University/Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases/NHC Key Laboratory for Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi 832002, China
2. Department of Respiratory Medicine, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi 832002, China

Received:2022-04-11 Revised:2022-08-12 Published:2023-02-15 Online:2022-09-30
Contact: HE Fang

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摘要/Abstract

摘要： 背景临床中对于高血压靶器官损害主要以全身降压辅以局部用药治疗为主，但因各组织对药物的反应不同甚至相斥，治疗效果不佳。现已关注到钙敏感受体（CaSR）与高血压的关系，然而其在高血压视网膜疾病中的作用和机制仍缺乏相关研究。目的探讨CaSR在高血压视网膜中的表达水平以及其与高血压心肌重塑、视网膜血管改变的关系。方法 2021年5—12月选取10只8周龄健康正常血压大鼠（WKY）作为WKY组，20只同周龄同源的自发性高血压大鼠（SHR）随机分为SHR组及抑制剂（SHR+NPS2143）组。SHR+NPS2143组腹腔注射CaSR抑制剂NPS2143，WKY组和SHR组注射等量的0.9%氯化钠溶液，共注射16周。干预0周、16周通过无创血压仪监测大鼠血压；干预0周、16周分别选取5只大鼠处死，通过马松（Masson）染色观察大鼠心肌胶原沉积，通过苏木素-伊红（HE）染色检测视网膜病理变化；通过免疫组织化学染色、实时荧光定量PCR（qRT-PCR）观察CaSR和血管内皮生长因子A（VEGFA）在视网膜的分布和表达。结果 SHR组干预0周、16周收缩压（SBP）、舒张压（DBP）、平均动脉压（MAP）高于WKY组（P<0.05）；SHR组干预16周SBP、DBP、MAP均低于SHR+NPS2143组（P<0.05）；SHR组、SHR+NPS2143组干预16周SBP、DBP、MAP均高于干预0周（P<0.05）。SHR组干预16周心脏/体质量（HW/BW%）和左心室/体质量（LVW/BW%）、心肌组织胶原容积分数（CVF）高于WKY组，低于SHR+NPS2143组（P<0.05）；SHR组、SHR+NPS2143组干预16周HW/BW%、LVW/BW%、CVF高于干预0周（P<0.05）。SHR组干预0周、16周视网膜总厚度、内丛状层厚度高于WKY组（P<0.05）；SHR组干预16周视网膜总厚度、内丛状层厚度低于SHR+NPS2143组（P<0.05）；SHR组干预16周视网膜内核层厚度高于WKY组、低于SHR+NPS2143组（P<0.05）。干预16周SHR组视网膜中CaSR低于WKY组、高于SHR+NPS2143组（P<0.05）；SHR组视网膜中VEGFA高于WKY组、低于SHR+NPS2143组（P<0.05）。结论应用CaSR抑制剂，可减少CaSR活化，促进视网膜中VEGFA表达增加，加剧高血压引起的心肌重塑与视网膜血管病变的发展。

关键词: 原发性高血压, 受体，钙敏感, 血管内皮生长因子, 视网膜血管, 心肌重塑, 大鼠

Abstract:

Background

Clinical treatment of target organ damage in hypertension is mainly based on systemic hypotension supplemented by topical medication, but the treatment is unsatisfactory due to different or even mutually exclusive responses of tissues to the drugs. The relationship between calcium-sensing receptors (CaSR) and hypertension has been investigated, however, studies on their role and mechanisms in hypertensive retinal disease are still lacking.

Objective

To investigate the expression level of CaSR in hypertensive retina and its relationship with myocardial remodeling and retinal vascular changes in hypertension.

Methods

Ten 8-week-old healthy wistar-kyoto rats (WKY) were selected as the WKY group, and 20 homologous spontaneous hypertensive rats (SHR) of the same age were randomly divided into SHR group and inhibitor (SHR+NPS2143) group from May to December 2021. During a 16-week intervention, the SHR+NPS2143 group received intraperitoneal injection of CaSR inhibitor NPS2143, while WKY and SHR groups were intraperitoneally injected with the equal volume of normal saline. At baseline and the end of intervention, blood pressure was measured by non-invasive blood pressure monitor in all rats, and from each group, five rats were selected and executed, and myocardial and retinal tissues were taken out for testing. Masson's Trichrome staining was used to measure the collagen deposition in the myocardium. H & E staining was used to detect the pathological changes in retinal tissues. The distribution and expression of CaSR and vascular endothelial growth factor A (VEGFA) in retinal tissues were detected using immunohistochemical staining and qRT-PCR.

Results

SHR group had significantly higher levels of systolic blood pressure (SBP) , diastolic blood pressure (DBP) and mean arterial pressure (MAP) than WKY group either at baseline or the end of intervention (P<0.05) . SHR group had much lower levels of SBP, DBP and MAP levels than SHR+NPS2143 group at the end of intervention (P<0.05) . At the end of the intervention, a significant growth was found in SBP, DBP and MAP levels in both SHR and SHR+NPS2143 groups (P<0.05) . Compared with SHR group, heart weight/body weight ratio (HW/BW%) , left ventricle weight/body weight ratio (LVW/BW%) , and myocardial collagen volume fraction (CVF) were significantly decreased in WKY group but increased significantly in SHR+NPS2143 group (P<0.05) . A significant growth was found in HW/BW%, LVW/BW% and CVF in both SHR and SHR+NPS2143 groups (P<0.05) . The total retinal thickness and inner plexiform layer thickness were higher in SHR group than in WKY group at baseline and 16 weeks of intervention (P<0.05) . The total retinal thickness and inner plexiform layer thickness were lower in the SHR group than in the SHR+NPS2143 group at 16 weeks of intervention (P<0.05) . Compared with SHR group, the inner plexiform layer thickness at 16 weeks of intervention was decreased in WKY group and increased in SHR+NPS2143 group (P<0.05) . CaSR in the retina of SHR group was lower than that of WKY group but higher than that of SHR+NPS2143 group (P<0.05) at 16 weeks of intervention. VEGFA in the retina of SHR group was higher than that of WKY group but lower than that of SHR+NPS2143 group (P<0.05) at 16 weeks of intervention.

Conclusion

The use of CaSR inhibitor could reduce the activation of CaSR, increase the expression of VEGFA in the retina, exacerbate hypertension-induced myocardial remodeling and the development of retinal vasculopathy.

Key words: Essential hypertension, Receptors, calcium-sensing, Vascular endothelial growth factor, Retinal vessels, Myocardial remodeling, Rats

赵佳琪,刘薇,唐娜,等. 钙敏感受体在高血压大鼠心肌重塑和视网膜血管病变中的作用研究[J]. 中国全科医学, 2023, 26(05): 576-582. DOI: 10.12114/j.issn.1007-9572.2022.0520.
ZHAO Jiaqi,LIU Wei,TANG Na, et al. Role of Calcium-sensing Receptors in Myocardial Remodeling and Retinal Vasculopathy in Rat Models of Hypertension[J]. Chinese General Practice, 2023, 26(05): 576-582. DOI: 10.12114/j.issn.1007-9572.2022.0520.

图/表 8

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基因	引物序列（5'—3'）
GAPDH	F：GACATGCCGCCTGGAGAAAC
	R：AGCCCAGGATGCCCTTTAGT
VEGFA	F：CCCTGGCTTTACTGCTGTACC
	R：CTTCATGGGCTTTCTGCTCCC
CaSR	F：ACGAGCCTCAGAAGAATGCC
	R：TCCGCATCTGCACACTGTAG

基因	引物序列（5'—3'）
GAPDH	F：GACATGCCGCCTGGAGAAAC
	R：AGCCCAGGATGCCCTTTAGT
VEGFA	F：CCCTGGCTTTACTGCTGTACC
	R：CTTCATGGGCTTTCTGCTCCC
CaSR	F：ACGAGCCTCAGAAGAATGCC
	R：TCCGCATCTGCACACTGTAG

组别	只数	SBP				DBP				MAP
组别	只数	干预0周	干预16周	t_配对值	P值	干预0周	干预16周	t_配对值	P值	干预0周	干预16周	t_配对值	P值
WKY组	5	107±1	108±1	0.260	0.999	92±6	101±10	1.744	0.575	95±3	103±6	1.973	0.479
SHR组	5	116±1^a	170±6^ab	22.610	<0.001	108±5^a	141±10^ab	5.610	0.002	111±3^a	150±9^ab	8.959	<0.001
SHR+NPS2143组	5	116±4	184±1	25.280	<0.001	109±2	169±6	9.332	<0.001	112±1	174±4	12.950	<0.001
F值		124.500	259.300			12.910	30.420			30.220	57.880
P值		<0.001	<0.001			0.007	0.010			0.004	0.004

组别	只数	SBP				DBP				MAP
组别	只数	干预0周	干预16周	t_配对值	P值	干预0周	干预16周	t_配对值	P值	干预0周	干预16周	t_配对值	P值
WKY组	5	107±1	108±1	0.260	0.999	92±6	101±10	1.744	0.575	95±3	103±6	1.973	0.479
SHR组	5	116±1^a	170±6^ab	22.610	<0.001	108±5^a	141±10^ab	5.610	0.002	111±3^a	150±9^ab	8.959	<0.001
SHR+NPS2143组	5	116±4	184±1	25.280	<0.001	109±2	169±6	9.332	<0.001	112±1	174±4	12.950	<0.001
F值		124.500	259.300			12.910	30.420			30.220	57.880
P值		<0.001	<0.001			0.007	0.010			0.004	0.004

组别	只数	HW/BW%				LVW/BW%				CVF
组别	只数	干预0周	干预16周	t_配对值	P值	干预0周	干预16周	t_配对值	P值	干预0周	干预16周	t_配对值	P值
WKY组	5	0.320±0.006	0.340±0.006	2.909	0.094	0.230±0.010	0.240±0.003	1.401	0.644	3.06±0.52	3.06±0.04	0.001	0.999
SHR组	5	0.330±0.002	0.370±0.001^ab	6.898	0.001	0.220±0.011	0.280±0.008^ab	6.672	<0.001	2.93±0.64	7.41±0.54^ab	3.834	0.032
SHR+NPS2143组	5	0.330±0.003	0.390±0.008	3.803	0.026	0.240±0.011	0.310±0.005	4.880	0.002	2.74±0.37	9.90±0.03	4.577	0.013
F值		3.610	2.235			1.065	58.590			0.097	122.600
P值		0.159	0.002			0.447	<0.001			0.910	0.001

钙敏感受体在高血压大鼠心肌重塑和视网膜血管病变中的作用研究

Role of Calcium-sensing Receptors in Myocardial Remodeling and Retinal Vasculopathy in Rat Models of Hypertension

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图/表 8

参考文献 25

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组别	CaSR	VEGFA
WKY组	1±0	1±0
SHR组	0.35±0.03^ab	3.82±0.53^ab
SHR+NPS2143组	0.13±0.02	11.48±0.56
t值	1223	383
P值	<0.001	<0.001

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组别	只数	视网膜总厚度				视网膜内丛状层厚度				视网膜内核层厚度
组别	只数	干预0周	干预16周	t_配对值	P值	干预0周	干预16周	t_配对值	P值	干预0周	干预16周	t_配对值	P值
WKY组	5	56.08±4.69	95.01±1.36	14.430	<0.001	12.59±1.99	22.23±1.69	4.544	0.002	5.81±0.63	12.09±1.21	6.650	<0.001
SHR组	5	72.18±9.02^a	112.89±8.69^ab	12.290	<0.001	19.76±0.51^a	33.94±3.16^ab	6.744	<0.001	7.45±0.57	15.59±1.05^ab	11.180	<0.001
SHR+NPS2143组	5	70.63±2.63	193.24±29.15	36.670	<0.001	19.33±0.58	55.33±9.95	17.120	<0.001	7.87±0.96	25.27±2.46	22.810	<0.001
F值		9.796	222.700			138.700	45.340			1.062	84.190
P值		0.029	<0.001			<0.001	<0.001			0.413	0.001

组别	只数	视网膜总厚度				视网膜内丛状层厚度				视网膜内核层厚度
组别	只数	干预0周	干预16周	t_配对值	P值	干预0周	干预16周	t_配对值	P值	干预0周	干预16周	t_配对值	P值
WKY组	5	56.08±4.69	95.01±1.36	14.430	<0.001	12.59±1.99	22.23±1.69	4.544	0.002	5.81±0.63	12.09±1.21	6.650	<0.001
SHR组	5	72.18±9.02^a	112.89±8.69^ab	12.290	<0.001	19.76±0.51^a	33.94±3.16^ab	6.744	<0.001	7.45±0.57	15.59±1.05^ab	11.180	<0.001
SHR+NPS2143组	5	70.63±2.63	193.24±29.15	36.670	<0.001	19.33±0.58	55.33±9.95	17.120	<0.001	7.87±0.96	25.27±2.46	22.810	<0.001
F值		9.796	222.700			138.700	45.340			1.062	84.190
P值		0.029	<0.001			<0.001	<0.001			0.413	0.001