慢性肾脏病大鼠主动脉钙化模型的术式优化及效果评价

doi:10.12300/j.issn.1674-5817.2024.128

实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (3): 279-289.DOI: 10.12300/j.issn.1674-5817.2024.128

慢性肾脏病大鼠主动脉钙化模型的术式优化及效果评价

潘颐聪(), 蒋汶洪()(), 胡明, 覃晓

广西医科大学第一附属医院血管外科, 南宁 530021

收稿日期:2024-08-28 修回日期:2024-12-18 出版日期:2025-07-07 发布日期:2025-06-25
通讯作者: 蒋汶洪（1989—），男，博士研究生，主治医师，课题负责人，研究方向：外周血管疾病。E-mail： jwhongxszy@163.com。ORCID： 0000-0001-6677-4533
作者简介:潘颐聪（1988—），男，博士研究生，研究方向：血管钙化。 E-mail： 375752640@qq.com。ORCID： 0009-0004-6758-9507
基金资助:
广西自然科学基金项目“基于骨桥蛋白（OPN）磷酸化表观修饰探讨抗酒石酸酸性磷酸酶（ACP5）在主动脉钙化调控中的作用模式和机理”(2022GXNSFBA035502)

Optimization of Surgical Procedure and Efficacy Evaluation of Aortic Calcification Model in Rats with Chronic Kidney Disease

PAN Yicong(), JIANG Wenhong()(), HU Ming, QIN Xiao

Department of Vascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China

Received:2024-08-28 Revised:2024-12-18 Published:2025-06-25 Online:2025-07-07
Contact: JIANG Wenhong (ORCID: 0000-0001-6677-4533), E-mail: jwhongxszy@163.com

摘要/Abstract

摘要：

目的通过不同的肾脏切除手术方法建立SD大鼠慢性肾脏病主动脉钙化模型，并进行手术时间及存活时间比较和效果评价，以探索更优化的建模方法。方法根据不同手术方式分为腹腔入路先切2/3左肾后二期右全肾切除组（A组）、腹腔入路2/3左肾及右全肾同时切除组（B组）、背入路先切右全肾后二期2/3左肾切除组（C组）、背入路先切2/3左肾后二期切除右全肾组（D组）共4组，比较腹腔入路及背入路、分期及一次性肾脏切除术的SD大鼠生存曲线确定最优的肾脏切除手术方式后，选取24只8周龄雄性SPF级SD大鼠进行肾脏切除联合骨化三醇钙化诱导：其中实验组12只大鼠行背入路的左侧2/3肾切除后右侧全肾切除术，1周后腹腔注射骨化三醇溶液1 μg/kg，以进行主动脉钙化诱导；对照组12只大鼠行假手术后1周，腹腔注射含1%DMSO的生理盐水250 μL/kg。腹腔注射药物3个月后，观察各组大鼠的存活情况。麻醉状态下，采集各组大鼠的血液样本，测定血清磷和钙离子浓度、血清尿素氮和肌酐含量。安乐死大鼠后进行剖检，肉眼观察残余肾脏形态，HE染色观察肾冠状切面的病理学变化。另外取各组大鼠的全主动脉，茜素红S及von Kossa染色观察主动脉钙化程度，实时荧光定量PCR法检测大鼠主动脉组织中平滑肌肌动蛋白相关蛋白α （smooth muscle actin-associated protein α ，Sm22）、Runt相关转录因子2（Runt-related transcription factor 2，Runx2）、骨桥蛋白（osteopontin，OPN）基因表达情况，以评价建模效果。结果不同术式优化探索实验发现，背入路先切除2/3左肾再切除右侧全肾的D组大鼠的存活率最高，提示该术式是建立肾功能不全的慢性肾脏病模型的最佳手术方式。运用该术式联合高剂量骨化三醇注射的实验组大鼠血清钙离子浓度显著低于假手术对照组（P＜0.05），而血清磷离子浓度、血清肌酐及血清尿素氮含量则显著高于对照组（P＜0.05）。肾脏HE染色可见实验组大鼠肾脏发生明显器质性改变，其中实验组大鼠的肾小球计数比对照组明显减少（P＜0.05），提示肾衰竭模型成功建立。茜素红S染色可见实验组大鼠的主动脉中膜中有明显的色素沉着，von Kossa染色可见实验组大鼠的主动脉中膜层明显有硝酸银沉积，符合肾衰竭主动脉钙化的表现。实时荧光定量PCR表明，实验组大鼠的主动脉组织中Sm22表达水平下降（P＜0.05），OPN和Runx2表达水平上升（P＜0.05），提示主动脉平滑肌细胞由平滑肌表型向骨样表型转变，主动脉钙化模型诱导成功。结论采用背入路先切除2/3左肾，再进行右侧全肾切除，联合高剂量骨化三醇溶液摄入的方法，可成功建立SD大鼠慢性肾脏病主动脉钙化模型。该方案能缩短手术时间，提高建模成功率和动物存活率。

关键词: 血管钙化, 慢性肾脏病, 肾脏切除术, 动物模型, SD大鼠

Abstract:

Objective To establish a chronic kidney disease-associated aortic calcification model in SD rats using different nephrectomy surgical methods, and to compare and evaluate surgical duration and survival time to explore a more optimized modeling method. Methods According to different surgical methods, the SD rats were divided into four groups: Group A: intraperitoneal resection of 2/3 of the left kidney followed by right total nephrectomy in the second stage; Group B: intraperitoneal resection of 2/3 of the left kidney and simultaneous right total nephrectomy; Group C: dorsal approach right total nephrectomy followed by resection of 2/3 of the left kidney in the second stage; Group D: dorsal approach resection of 2/3 of the left kidney followed by right total nephrectomy in the second stage. After comparing survival curves of SD rats undergoing intraperitoneal versus dorsal approaches, and staged versus single-stage nephrectomy, the optimal nephrectomy surgical method was determined. Then, twenty-four 8-week-old SPF-grade male SD rats were selected for nephrectomy combined with calcitriol-induced calcification. Experimental group (12 rats): the dorsal approach left 2/3 nephrectomy followed by right total nephrectomy, with intraperitoneal injection of 1 μg/kg calcitriol administered one week later to induce aortic calcification. Control group (12 rats): the intraperitoneal injection of 250 μL/kg physiological saline containing 1% DMSO one week after sham surgery. After intraperitoneal injection of drugs for 3 months, the survival status of rats in each group was observed. Under anesthesia, blood samples were collected from each group to measure serum phosphorus and calcium ion concentrations, as well as serum urea nitrogen and creatinine levels. After euthanizing the rats, a post-mortem examination was performed to observe the residual kidney morphology, and HE staining was used to observe the pathological changes in the coronal section of the kidney. Additionally, the entire aorta of each group was taken, and the degree of aortic calcification was observed by staining with Alizarin red S and von Kossa. Real-time fluorescence quantitative PCR was used to detect the gene expression of smooth muscle actin-associated protein alpha (Sm22), Runt-related transcription factor 2 (Runx2), and osteopontin (OPN) in rat aortic tissue to evaluate the effectiveness of the model. Results The exploratory optimization experiment of different surgical procedures found that the survival rate of group D rats,which underwent 2/3 left kidney resection followed by right whole kidney resection via the dorsal approach, was the highest, indicating that this surgical procedure was the best method for establishing a chronic kidney disease model with renal dysfunction. The experimental group rats treated with this surgical procedure combined with high-dose calcitriol injection had significantly lower serum calcium ion concentration than those in the sham-operated control group (P<0.05), while serum phosphorus ion concentration, serum creatinine, and serum urea nitrogen levels were significantly higher than those of the control group (P<0.05). HE staining of the kidneys showed significant organic changes in the kidneys of the experimental group rats, with a significant decrease in glomerular count compared to that of the control group (P<0.05), indicating the successful establishment of a renal failure model. Alizarin red S staining showed significant pigment deposition in the aortic media of the experimental group rats, while von Kossa staining showed significant silver nitrate deposition in the aortic media of the experimental group rats, which was consistent with the manifestation of aortic calcification in renal failure. Real-time fluorescence quantitative PCR showed that the expression level of Sm22 in the aortic tissue of the experimental group rats decreased (P<0.05), while the expression levels of OPN and Runx2 increased (P<0.05), indicating a transition of aortic smooth muscle cells from smooth muscle phenotype to bone-like phenotype and successful induction of an aortic calcification model. Conclusion The method of establishing an aortic calcification model of chronic kidney disease in SD rats by first removing two-thirds of the left kidney via the dorsal approach followed by right total nephrectomy, combined with high-dose calcitriol administration, shortens the surgical time, improves the success rate of modeling, and increases the animal survival rate.

Key words: Vascular calcification, Chronic kidney disease, Nephrectomy, Animal models, SD rats

中图分类号:

Q95-33

潘颐聪,蒋汶洪,胡明,等. 慢性肾脏病大鼠主动脉钙化模型的术式优化及效果评价[J]. 实验动物与比较医学, 2025, 45(3): 279-289. DOI: 10.12300/j.issn.1674-5817.2024.128.

PAN Yicong,JIANG Wenhong,HU Ming,et al. Optimization of Surgical Procedure and Efficacy Evaluation of Aortic Calcification Model in Rats with Chronic Kidney Disease[J]. Laboratory Animal and Comparative Medicine, 2025, 45(3): 279-289. DOI: 10.12300/j.issn.1674-5817.2024.128.

图/表 7

图1 SD大鼠慢性肾脏病主动脉钙化建模及评价实验流程图注：8周龄SD大鼠饲养于SPF级动物屏障设施，常规饮食适应3 d后进行左肾2/3切除术，术后常规饲养，1周后进行右肾切除术。1周后每3 d给予1 μg/kg骨化三醇注射液。注射12周后进行静脉采血，并对全主动脉及肾脏进行取材，血清用于血生化检测，肾脏行冠状面石蜡切片后进行HE染色，主动脉一部分制成石蜡切片进行茜素红S染色、von Kossa染色，一部分进行冻存用于实时荧光定量PCR检测。

Figure1 Flowchart of the experimental process for modeling and evaluating aortic calcification in SD rats with chronic kidney diseaseNote：Eight-week-old SD rats were housed in SPF-grade animal barrier facilities and underwent left kidney two-thirds nephrectomy after three days of regular dietary adaptation. After surgery， they were routinely housed and underwent right kidney nephrectomy one week later. After one week， administer 1 μg/kg calcitriol injection every three days. After 12 weeks of injection， venous blood collection was performed， and samples were taken from the entire aorta and kidneys. Serum was used for blood biochemistry testing， and paraffin-embedded kidneys were sectioned in coronal side for HE staining. A portion of the aorta was sectioned in paraffin for Alizarin Red S staining and von Kossa staining， and a portion was frozen for real-time fluorescence quantitative PCR detection.

表1 PCR引物序列信息

Table 1 Primers for real-time fluorescent quantitative PCR

目标基因名称 Target gene name	NCBI基因序列号 NCBI reference sequence	引物序列信息 Primer sequence information	扩增片段大小/bp Amplification fragment size/bp
Sm22 (Tagln)	NC-086026.1	F：5’-CAGATGGAACAGGTGGCTCAA-3’	161
		R：5’-GCCCAAAGCCATTACAGTCCTC-3’
OPN (Spp1)	NC-086032.1	F：5’-GCCGAGGTGATAGCTTGGCTTA-3’	145
		R：5’-TTGATAGCCTCATCGGACTCCTG-3’
Runx2	NC-086027.1	F：5’-GGATGCCTTAGTGCCCAAATG-3’	120
		R：5’-CACCCTGTGAGGTGGCTGAA-3’
β-actin	NC-086030.1	F：5’-CACCCGCGAGTACAACCTTC-3’	207
		R：5’-CCCATACCCACCATCACACC-3’

图2 不同手术方式构建的慢性肾功能不全模型组大鼠的Kaplan-Meier生存曲线分析注：横坐标表示切除两侧肾脏后第2天开始记录的时间（单位为天）。上图展示了接受不同方式手术的大鼠术后60 d累积生存率（Log-Rank检验，P=0.007 7），其中D组大鼠的存活率最高，与A、B、C组相比差异有统计学意义（P值分别为0.003 0、0.007 4、0.003 0），而且A、B、C组的大鼠均在术后10 d内大量死亡。

Figure 2 Kaplan-Meier survival curve analysis of rats in chronic renal insufficiency model groups constructed using different surgical methodsNote： The horizontal axis represents the time （in days） recorded from the second day after the removal of both kidneys. Upper of the figure shows that there is a significant difference in the cumulative survival rate of rats after 60 days of surgery using different surgical methods （log-rank test， P=0.007 7）， The survival rate of rats in group D was the highest， with statistically significant differences compared to groups A， B， and C （P=0.003 0， P=0.007 4， P=0.003 0， respectively）. Moreover， rats in groups A， B， and C experienced high mortality within 10 days after surgery.

表2 实验组与对照组大鼠血清生化指标对比 (xˉ±s)

Table 2 Comparison of biochemical indicators between the experimental group and the control group

血生化指标 Biochemistry index	实验组（n=9） Experimental group	对照组（n=12） Control group	t值 t value	P值 P value
血清钙 c/(mmol·L^-1) Serum calcium ions	1.876±0.036	1.929±0.042	3.431	0.004
血清磷c/(mmol·L^-1) Serum phosphate ions	2.059±0.333	1.580±0.271	3.046	0.014
血清肌酐c/(μmol·L^-1) Serum creatinine	119.960±35.640	21.164±8.076	8.984	<0.000 1
血清尿素氮c/(mmol·L^-1) Serum urea nitrogen	57.991±8.745	22.609±8.058	6.895	<0.000 1

图3 实验组与对照组大鼠的肾脏HE染色观察注：实验组是肾脏切除术+骨化三醇钙化诱导3个月的大鼠肾脏，对照组为假手术+DMSO注射3个月的大鼠肾脏。图中白色箭头指示肾小球。实验组（CI组，n=9）的肾小球数量显著少于对照组（Sham组，n=12），***P<0.001。

Figure 3 HE staining observation of kidneys from rats in the experimental and control groupsNote： The experimental group consisted of rats undergoing nephrectomy and calcitriol calcification induction for 3 months， while the control group consisted of rats undergoing sham surgery and DMSO injection for 3 months. The white arrow in the picture represents the glomerulus. The number of glomeruli in the experimental group （CI group， n=9） was significantly less than that in the control group （sham group， n=12），***P<0.001.

图4 实验组和对照组大鼠的主动脉von Kossa染色及茜素红S染色观察注：IN表示主动脉内膜；ME表示主动脉中膜；AD表示主动脉外膜。图A、B为von Kossa染色；图C、D为茜素红S染色。实验组（CI，n=9）的染色面积占比明显大于对照组（sham，n=12）（***P<0.001）。白色箭头处为高倍镜下动脉中膜钙化沉积。

Figure 4 Observation of von Kossa and Alizarin red S staining in the aorta of rats from the experimental and control groupsNote： IN represents the intima of the aorta； ME stands for the media of the aortic； AD represents the adventitia of the aorta. Figures A and B show von Kossa staining； Figures C and D show Alizarin red S staining. The proportion of stained area in the experimental group （CI， n=9） was significantly larger than that in the control group （sham， n=12）（***P<0.001）. The white arrow indicates arterial media calcification deposition under high magnification view.

图5 实时荧光定量PCR检测实验组和对照组大鼠的主动脉组织细胞中OPN、Runx2及Sm22基因表达注：相较于对照组（sham），实验组（CI）中反映血管平滑肌成骨样分化表型的OPN及Runx2相对表达量明显增加（*P<0.05，**P<0.01），而反映血管平滑肌收缩表型的Sm22表达量减少（***P<0.001）。

Figure 5 Real-time fluorescence quantitative PCR detection of OPN， Runx2， and Sm22 gene expression in aortic tissue of rats from the experimental and control groupsNote： Compared with the control group （sham）， the expression level of Sm22， which reflects the vascular smooth muscle contraction phenotype， decreased in the experimental group （CI）（***P<0.001）， while the expression levels of OPN and Runx2， which reflects the osteogenic differentiation phenotype of vascular smooth muscle， increased significantly （ * P<0.05， ** P<0.01）.

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慢性肾脏病大鼠主动脉钙化模型的术式优化及效果评价

Optimization of Surgical Procedure and Efficacy Evaluation of Aortic Calcification Model in Rats with Chronic Kidney Disease

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