复方肾怡治疗狼疮肾炎小鼠的疗效及对补体旁路途径激活的研究

doi:10.12114/j.issn.1007-9572.2022.0301

中国全科医学 ›› 2022, Vol. 25 ›› Issue (26): 3298-3307.DOI: 10.12114/j.issn.1007-9572.2022.0301

所属专题：泌尿系统疾病最新文章合集

复方肾怡治疗狼疮肾炎小鼠的疗效及对补体旁路途径激活的研究

陈铿¹^,², 邓翼遥³, 尚顺来², 李清刚², 陈香美¹^,²^,^*()

1．510006　广东省广州市，广东药科大学临床医学院
2．100853　北京市，中国人民解放军总医院第一医学中心肾脏病医学部　解放军肾脏病研究所　肾脏疾病国家重点实验室　国家慢性肾病临床医学研究中心　肾脏疾病研究北京市重点实验室
3．550002　贵州省贵阳市，贵州省人民医院肾内科

收稿日期:2022-02-28 修回日期:2022-06-10 出版日期:2022-09-15 发布日期:2022-07-06
通讯作者: 陈香美
作者贡献：陈铿进行研究的设计及实施，研究数据的收集及整理、统计分析、绘制图表，文章的构思及撰写；邓翼遥进行研究的规划设计及论文修订；尚顺来进行部分数据整理；李清刚、陈香美对研究提出概念并监督研究活动的规划和执行；陈香美负责最终版本修订，对论文负责。陈铿，邓翼遥，尚顺来，等.复方肾怡治疗狼疮肾炎小鼠的疗效及对补体旁路途径激活的研究[J].中国全科医学，2022，25（26）：3298-3307.[www.chinagp.net]
基金资助:
国家自然科学基金资助项目(81830019); 北京市自然科学基金资助项目(7202188)

Chinese Herbal Formula Shenyi Improves Kidney Injury and Inhibits the Activation of the Alternative Complement Pathway in a Mouse Model of Lupus Nephritis

Keng CHEN¹^,², Yiyao DENG³, Shunlai SHANG², Qinggang LI², Xiangmei CHEN¹^,²^,^*()

1. School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou 510006, China
2. Department of Nephrology, First Medical Center of Chinese PLA General Hospital/Nephrology Institute of the Chinese People's Liberation Army/State Key Laboratory of Kidney Diseases/National Clinical Research Center for Kidney Diseases/Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China
3. Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang 550002, China

Received:2022-02-28 Revised:2022-06-10 Published:2022-09-15 Online:2022-07-06
Contact: Xiangmei CHEN
About author:
CHEN K, DENG Y Y, SHANG S L, et al. Chinese herbal formula Shenyi improves kidney injury and inhibits the activation of the alternative complement pathway in a mouse model of lupus nephritis[J]. Chinese General Practice, 2022, 25 (26) : 3298-3307.

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摘要/Abstract

摘要： 背景狼疮肾炎（LN）是系统性红斑狼疮严重并发症之一，相关研究表明中药复方肾怡（SY）可以调节机体免疫及抑制肾脏纤维化。目前运用复方SY治疗LN的疗效及机制尚不清楚。目的探究复方SY对LN小鼠的治疗作用及补体旁路途径激活的影响。方法 2021年4—7月，选取35只SPF级MRL/lpr小鼠（8周龄）、6只SPF级C57BL/6J小鼠（8周龄）进行实验。将MRL/lpr小鼠依据随机数字表法分为MRL/lpr组（n=8）及SY低剂量组（n=9）、SY中剂量组（n=9）、SY高剂量组（n=9），C57BL/6J小鼠为正常对照组（n=6）。SY低、中、高剂量组分别以15.34、46.02、92.04 g/kg剂量进行复方SY汤剂灌胃，正常对照组及MRL/lpr组以0.5 ml 0.9%氯化钠溶液灌胃。从小鼠12周龄开始干预，1次/d，持续14周。观察各组动物体征，检测尿蛋白与肌酐比值（UPCR），血清抗双链DNA抗体（anti-dsDNA）、抗核抗体（ANA）水平，肾脏组织病理情况，肾脏组织C3、免疫球蛋白G（IgG）、C5b-9免疫沉积情况，肾脏组织α平滑肌肌动蛋白（α-SMA）、Ⅰ型胶原蛋白（CollagenⅠ）、Fibronectin及补体蛋白水平。结果截至干预结束，正常对照组6只小鼠存活，MRL/lpr组3只小鼠存活，SY低、中、高剂量组分别有5、7、9只小鼠存活。（1）正常对照组、SY中剂量组、SY高剂量组小鼠体征量化分值均低于MRL/lpr组（P<0.05）。（2）正常对照组、SY各剂量组小鼠干预第9、10、11、12、13周UPCR均低于MRL/lpr组（P<0.05）。（3）正常对照组、SY低剂量组、SY高剂量组小鼠干预14周后血清anti-dsDNA水平低于MRL/lpr组（P<0.05）；正常对照组、SY各剂量组小鼠干预14周后血清ANA水平低于MRL/lpr组（P<0.05）。（4）干预14周后，HE染色可见MRL/lpr组小鼠肾小球内有免疫复合物沉积，PAS染色可见肾小球内有新月体形成；HE染色可见SY各剂量组小鼠肾小球大致正常，而PAS染色可见SY中、高剂量组小鼠肾小球内有系膜细胞增生，伴少量炎细胞浸润。（5）正常对照组、SY各剂量组小鼠干预14周后肾脏组织C3、C5b-9沉积低于MRL/lpr组（P<0.05）；SY低剂量组、SY高剂量组小鼠干预14周后肾脏组织IgG免疫沉积低于MRL/lpr组（P<0.05）。（6）SY高剂量组小鼠干预14周后肾脏组织CollagenⅠ、Fibronectin 、C3、C5、CD35蛋白水平低于MRL/lpr组（P<0.05）；SY低、中剂量组小鼠干预14周后肾脏组织Fibronectin、C3、C5、CD35蛋白水平低于MRL/lpr组（P<0.05）；正常对照组小鼠干预14周后肾脏组织Fibronectin蛋白水平低于MRL/lpr组（P<0.05）。结论复方SY可改善MRL/lpr小鼠狼疮肾脏损伤，延缓疾病进展，其作用机制可能是通过抑制补体旁路途径的激活。

关键词: 狼疮性肾炎, 肾怡, 肾病药（中药）, 中草药, 补体, MRL/lpr小鼠

Abstract:

Background

Lupus nephritis (LN) is one of the serious complications of systemic lupus erythematosus. Relevant studies have shown that the traditional Chinese herbal formula Shenyi (SY) can regulate the body's immunity and inhibit renal fibrosis. At present, the efficacy and mechanism of using SY in the treatment of LN remains unclear.

Objective

To explore the therapeutic effect of compound SY on LN mice and the activation of the alternative complement pathway.

Methods

From April to July 2021, 35 SPF MRL/lpr mice (8 weeks old) and 6 SPF C57BL/6J mice (8 weeks old) were selected for experiments. MRL/lpr mice were randomly divided into MRL/lpr group (n=8) and SY low dose group (n=9) , SY middle dose group (n=9) , SY high dose group (n=9) , C57BL/6J mice were normal control group (n=6) . The low, the medium and high dose groups of SY were respectively administrated with SY decoction at the doses of 15.34, 46.02 and 92.04 g/kg by gavage. The normal control group and MRL/lpr group were respectively administrated with 0.5 ml 0.9 % sodium chloride solution by gavage. Intervention started at 12 weeks of age, once a day for 14 weeks. The animal signs, urinary protein to creatinine ratio (UPCR) , anti-dsDNA antibody (anti-dsDNA) concentration, serum antinuclear antibody (ANA) concentration, renal tissue pathology, renal tissue C3, IgG, C5b-9 immune deposition, renal tissue α-SMA, CollagenⅠ, Fibronectin and complement protein levels were observed.

Results

At the end of the intervention, 6 mice in normal control group survived, 3 mice in MRL/lpr group survived, and 5, 7 and 9 mice in SY low, the medium and high dose groups survived, respectively. (1) The quantitative scores of the signs of mice in the normal control group, the middle-dose SY group, and the high-dose SY group were lower than those in the MRL/lpr group (P<0.05) . (2) The UPCR in the normal control group and the SY dose groups at the 9th, 10th, 11th, 12th, and 13th weeks of intervention were lower than those in the MRL/lpr group (P<0.05) . (3) The serum anti-dsDNA levels in the normal control group, the low-dose SY group, and the high-dose SY group were lower than those in the MRL/lpr group after 14 weeks of intervention (P<0.05) . After 14 weeks of intervention, the serum ANA levels of mice in the normal control group and SY dose groups were lower than those in the MRL/lpr group (P<0.05) . (4) After 14 weeks of intervention, HE staining showed the deposition of immune complexes in the glomeruli of the MRL/lpr group mice, and PAS staining showed the formation of crescents in the glomeruli. HE staining showed that the glomeruli of mice in each dose group of SY were generally normal, while PAS staining showed that there were mesangial cell proliferation and a small amount of inflammatory cell infiltration in the glomeruli of the mice in the middle and high dose groups of SY. (5) The deposition of C3 and C5b-9 in the kidney tissue of mice in the normal control group and SY dose groups after 14 weeks of intervention was lower than that in the MRL/lpr group (P<0.05) . After 14 weeks of intervention, the IgG immune deposition in renal tissue of low-dose SY group and high-dose SY group was lower than that of MRL/lpr group (P<0.05) . (6) The protein levels of Collagen Ⅰ, Fibronectin, C3, C5, CD35 in kidney tissue of mice in high-dose SY group were lower than those in MRL/lpr group after 14 weeks of intervention (P<0.05) . After 14 weeks of intervention, the protein levels of Fibronectin, C3, C5 and CD35 in renal tissues of low-dose and medium-dose SY groups were lower than those in MRL/ LPR group (P<0.05) . After 14 weeks of intervention, the level of Fibronectin protein in the kidney tissue of mice in the normal control group was lower than that in the MRL/lpr group (P<0.05) .

Conclusion

SY can ameliorate lupus renal injury in MRL/lpr mice and delay disease progression, and its mechanism of action may be by inhibiting the activation of the alternative complement pathway.

Key words: Lupus nephritis, Shenyi, Renal agents (TCD), Drugs, Chinese herbal, Complement, MRL/lpr mice

陈铿,邓翼遥,尚顺来,等. 复方肾怡治疗狼疮肾炎小鼠的疗效及对补体旁路途径激活的研究[J]. 中国全科医学, 2022, 25(26): 3298-3307. DOI: 10.12114/j.issn.1007-9572.2022.0301.
Keng CHEN,Yiyao DENG,Shunlai SHANG, et al. Chinese Herbal Formula Shenyi Improves Kidney Injury and Inhibits the Activation of the Alternative Complement Pathway in a Mouse Model of Lupus Nephritis[J]. Chinese General Practice, 2022, 25(26): 3298-3307. DOI: 10.12114/j.issn.1007-9572.2022.0301.

图/表 12

图1 26周龄不同组小鼠的体征图注：A为小鼠头面部体征，B为小鼠躯干体征，C为实验终点时小鼠脾脏长度；SY=肾怡

Figure 1 Signs of 26-week-old mice in five groups

表1 5组小鼠体征量化分值比较（±s，分）

Table 1 Comparison of quantitative scores of signs of mice in five groups

组别	只数	体征量化分值
正常对照组	6	-4.73±1.69^a
MRL/lpr组	3	5.37±2.04
SY低剂量组	5	1.46±1.51
SY中剂量组	7	-2.13±2.23^a
SY高剂量组	9	-0.15±2.49^a
F值		13.96
P值		<0.001

表2 5组小鼠干预第9、10、11、12、13周UPCR比较（±s）

Table 2 Comparison of UPCR among 5 groups at 9，10，11，12 and 13 weeks after intervention

组别	只数	干预第9周	干预第10周	干预第11周	干预第12周	干预第13周
正常对照组	6	0.20±0.11^a	0.40±0.02^a	0.28±0.03^a	0.19±0.07^a	0.39±0.05^a
MRL/lpr组	3	0.69±0.26	0.88±0.33	0.84±0.30	0.90±0.12	0.90±0.17
SY低剂量组	5	0.32±0.02^a	0.46±0.06^a	0.36±0.07^a	0.27±0.10^a	0.45±0.10^a
SY中剂量组	7	0.27±0.03^a	0.43±0.14^a	0.36±0.04^a	0.45±0.25^a	0.43±0.05^a
SY高剂量组	9	0.25±0.07^a	0.52±0.24^a	0.33±0.05^a	0.34±0.14^a	0.46±0.09^a
F值		13.58	3.13	12.80	14.54	20.97
P值		<0.001	0.047	<0.001	<0.001	<0.001

表3 5组小鼠干预14周后血清anti-dsDNA、ANA水平比较（±s）

Table 3 Comparison of serum anti-dsDNA and ANA levels in five groups of mice after 14 weeks of intervention

组别	只数	anti-dsDNA	ANA
正常对照组	6	0.76±0.21^a	0.24±0.02^a
MRL/lpr组	3	1.53±0.04	0.50±0.06
SY低剂量组	5	1.18±0.06^a	0.34±0.04^a
SY中剂量组	7	1.59±0.05	0.33±0.04^a
SY高剂量组	9	1.19±0.16^a	0.34±0.02^a
F值		25.06	23.79
P值		<0.001	<0.001

图2 5组小鼠肾脏组织病理图（400×）

Figure 2 HE and PAS staining results of kidney tissue in each group of mice

表4 5组小鼠干预14周后肾脏组织C3、IgG、C5b-9免疫沉积比较

Table 4 Comparison of immune deposition of C3，IgG and C5b-9 in kidney tissue of 5 groups of mice after 14 weeks of intervention

组别	只数	C3（±s）	IgG〔M（P₂₅，P₇₅）〕	C5b-9（±s）
正常对照组	6	3.65±3.14^a	4.57（3.14，20.06）	0.00±0.00^a
MRL/lpr组	3	142.70±87.02	69.14（38.18，98.68）	0.34±0.13
SY低剂量组	5	0.41±0.48^a	1.22（0.82，1.51）^a	0.04±0.01^a
SY中剂量组	7	0.36±0.47^a	2.61（1.78，3.81）	0.13±0.03^a
SY高剂量组	9	0.14±0.04^a	1.10（0.92，1.21）^a	0.17±0.03^a
F（H）值		7.93	16.73^b	13.57
P值		0.004	0.002	<0.001

图3 5组小鼠肾脏组织C3荧光检测结果注：DAPI=4'，6-二脒基-2-苯基吲哚

Figure 3 Fluorescence detection of C3 deposition in kidney tissues of 5 groups of mice

图4 5组小鼠肾脏组织IgG荧光检测结果注：IgG=免疫球蛋白G

Figure 4 Fluorescence detection of IgG deposition in kidney tissues of 5 groups of mice

图5 5组动物肾脏组织C5b-9荧光检测结果

Figure 5 Fluorescence detection of C5b-9 deposition in kidney tissues of 5 groups of mice

表5 5组小鼠干预14周后肾脏组织α-SMA、CollagenⅠ、Fibronectin及补体蛋白水平比较（±s）

Table 5 Comparison of the levels of α-SMA，CollagenⅠ，fibronectin and complement protein in kidney tissue of 5 groups of mice after 14 weeks of intervention

组别	只数	α-SMA	CollagenⅠ	Fibronectin	C3	C5	CD35
正常对照组	6	0.66±0.32	0.59±0.08	0.19±0.04^a	0.69±0.30	0.82±0.34	0.37±0.05^a
MRL/lpr组	3	1.23±0.71	0.96±0.13	0.83±0.02	0.92±0.19	0.84±0.17	0.92±0.07
SY低剂量组	5	0.66±0.20	0.81±0.25	0.45±0.02^a	0.28±0.14^a	0.34±0.11^a	0.31±0.01^a
SY中剂量组	7	0.54±0.50	0.67±0.23	0.24±0.01^a	0.34±0.16^a	0.19±0.13^a	0.65±0.02^a
SY高剂量组	9	0.22±0.16^a	0.20±0.03^a	0.27±0.03^a	0.19±0.08^a	0.18±0.12^a	0.20±0.02^a
F值		2.19	8.80	281.60	7.99	8.86	156.50
P值		0.144	0.003	<0.001	0.004	0.003	<0.001

图6 SY对小鼠肾脏组织α-SMA、CollagenⅠ、Fibronectin及补体蛋白影响的电泳图注：α-SMA=α平滑肌肌动蛋白，CollagenⅠ=Ⅰ型胶原蛋白，GAPDH=甘油醛-3-磷酸脱氢酶

Figure 6 Electropherogram of the effect of Fufangshenyi Decoction on α-SMA，CollagenⅠ，fibronectin and complement proteins in the kidney tissue of the mouse model of lupus nephritis

图7 SY对小鼠肾脏组织补体蛋白调节的影响通路图

Figure 7 Pathway map of the effect of Fufangshenyi Decoction on the regulation of complement proteins in the kidney tissue of the mouse model of lupus nephritis

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复方肾怡治疗狼疮肾炎小鼠的疗效及对补体旁路途径激活的研究

Chinese Herbal Formula Shenyi Improves Kidney Injury and Inhibits the Activation of the Alternative Complement Pathway in a Mouse Model of Lupus Nephritis

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