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Based on Oxidative Stress/NF-
κ B Exploration of Mechanism of Modified Zhenwutang in Delaying Progression of Chronic Renal Failure Complicated with Cardiac Disease by Inflammatory Factors- Chinese Journal of Experimental Traditional Medical Formulae Vol. 29, Issue 16, Pages: 100-113(2023)
- 作者机构：
1.河北中医药大学 研究生学院，石家庄 050091
2.河北中医药大学 第一附属医院/河北省中医院，石家庄 050011
- 作者简介：
- 基金信息：
DOI：10.13422/j.cnki.syfjx.20230619
CLC： R284;R285;R289;R287;R22;R2-031;R33;R24Published：20 August 2023，
Published Online：19 May 2023，
Received：07 April 2023，
- 稿件说明：
扫 描 看 全 文
张圆圆,靳培培,宋婧雅等.基于OS/NF-κB/炎症因子探讨加味真武汤延缓慢性肾功能衰竭并发心脏病变进展的作用机制[J].中国实验方剂学杂志,2023,29(16):100-113.
ZHANG Yuanyuan,JIN Peipei,SONG Jingya,et al.Based on Oxidative Stress/NF-κB Exploration of Mechanism of Modified Zhenwutang in Delaying Progression of Chronic Renal Failure Complicated with Cardiac Disease by Inflammatory Factors[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(16):100-113.
张圆圆,靳培培,宋婧雅等.基于OS/NF-κB/炎症因子探讨加味真武汤延缓慢性肾功能衰竭并发心脏病变进展的作用机制[J].中国实验方剂学杂志,2023,29(16):100-113. DOI： 10.13422/j.cnki.syfjx.20230619.
ZHANG Yuanyuan,JIN Peipei,SONG Jingya,et al.Based on Oxidative Stress/NF-κB Exploration of Mechanism of Modified Zhenwutang in Delaying Progression of Chronic Renal Failure Complicated with Cardiac Disease by Inflammatory Factors[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(16):100-113. DOI： 10.13422/j.cnki.syfjx.20230619.
摘要
目的
2
通过观察加味真武汤对腺嘌呤诱导慢性肾功能衰竭大鼠血清及肾组织中超氧化物歧化酶1（SOD1）、丙二醛（MDA）、晚期氧化蛋白产物（AOPP）、核转录因子-
κ
B p65（NF-
κ
B p65）、磷酸化核转录因子-
κ
B p65（p-p65）、白细胞介素（IL）-1
β
、肿瘤坏死因子（TNF）-
α
表达及心肾组织病理的影响，探讨加味真武汤延缓慢性肾功能衰竭并发心脏病变进展的可能作用机制。
方法
2
将50只SPF级雄性SD大鼠按照随机数字表法分为正常组10只、造模组40只，将大鼠适应性饲养1周后采用腺嘌呤150 mg·kg
-1
·d
-1
灌胃的方法建立实验性慢性肾功能衰竭并发心血管病变大鼠模型。造模完成后随机选取正常组和造模组大鼠各3只取材，检测造模是否成功。造模成功后，将造模组大鼠按照随机数字表法分成模型组、加味真武汤低剂量组、加味真武汤中剂量组、加味真武汤高剂量组、盐酸贝那普利组各6只，进行药物灌胃，每日1次，治疗4周。于实验第17周末检测24 h尿蛋白定量（24 h-UTP）、尿肌酐（UCr），第17周末各组大鼠麻醉后取材，腹主动脉取血后离心取上清检测甘油三酯（TG）、总胆固醇（TC）、血钙、血钾、血磷、肌酐（Cr）、尿素氮（BUN）；酶联免疫吸附测定法（ELISA）检测血清AOPP、IL-1
β
、TNF-
α
表达水平变化；苏木素-伊红（HE）染色法/马松染色（Masson）法观察心肾组织病理改变；透射电镜观察近端肾小管超微结构变化；免疫组织化学（IHC）法观察肾组织SOD1、MDA、AOPP、NF-
κ
B p65、p-p65、IL-1
β
、TNF-
α
表达情况；实时荧光定量聚合酶链式反应法（Real-time PCR）观察肾组织SOD1、NF-
κ
B p65、IL-1
β
、TNF-
α
mRNA表达水平；蛋白质免疫印迹法（Western blot）检测肾组织SOD1、MDA、NF-
κ
B p65、p-p65表达水平。
结果
2
①与正常组比较，模型组实验大鼠24 h-UTP显著增高（
P
<
0.01），UCr显著降低（
P
<
0.01）；模型组实验大鼠Cr、BUN、TG、TC、血磷、血钾显著增高（
P
<
0.01）；模型组实验大鼠血清中AOPP、IL-1
β
、TNF-
α
含量显著升高（
P
<
0.01）；模型组实验大鼠肾小球球囊间隙明显增宽，肾间质明显增宽伴有大量炎细胞浸润，大量肾小管官腔有褐色沉淀物阻塞，肾间质有大量胶原纤维沉积，肾脏血管周围、肾小囊壁层囊壁外、肾小球基底膜和肾小管基底膜胶原纤维明显增多，心脏心肌纤维明显增粗，血管周围有少量炎细胞浸润，心脏血管周围和心肌细胞间有大量胶原纤维。模型组实验大鼠近端肾小管上皮细胞内可见高密度菱形针状结晶，溶酶体增多，线粒体增生、线粒体嵴和线粒体外膜致密变；模型组实验大鼠左心室舒张期心室壁厚度和收缩期心室壁厚度均升高；模型组实验大鼠MDA、AOPP、NF-
κ
B p65、IL-1
β
、TNF-
α
在近端肾小管上皮细胞表达明显增强（
P
<
0.01），p-p65在近端肾小管上皮细胞的细胞核表达明显增加（
P
<
0.01），SOD1在近端肾小管上皮细胞表达显著减弱（
P
<
0.01）；模型组实验大鼠肾组织NF-
κ
B p65、IL-1
β
、TNF-
α
mRNA表达显著增强（
P
<
0.01），SOD1 mRNA表达显著减弱（
P
<
0.01）；模型组实验大鼠肾组织SOD1蛋白表达显著下降（
P
<
0.01）；MDA、NF-
κ
B p65、p-p65蛋白表达显著升高（
P
<
0.01）。②与模型组比较，加味真武汤干预后，24 h-UTP显著降低（
P
<
0.01），UCr显著升高（
P
<
0.01）；Cr、BUN、TG、TC、血磷、血钾显著降低（
P
<
0.01）；血清AOPP、IL-1
β
、TNF-
α
含量显著下降（
P
<
0.01）；心肾病理损害减轻；近端肾小管上皮细胞线粒体损伤减轻；MDA、AOPP、NF-
κ
B p65、IL-1
β
、TNF-
α
在近端肾小管上皮细胞表达显著减弱（
P
<
0.01），p-p65在近端肾小管上皮细胞的细胞核表达显著减弱（
P
<
0.01），SOD1在近端肾小管上皮细胞表达显著增强（
P
<
0.01）；肾组织NF-
κ
B p65、IL-1
β
、TNF-
α
mRNA表达显著减少（
P
<
0.01），SOD1 mRNA表达显著升高（
P
<
0.01）；肾组织SOD1蛋白表达显著升高（
P
<
0.01），MDA、NF-
κ
B p65、p-p65蛋白表达显著降低（
P
<
0.01）；中药组表现出明显的量效趋势。
结论
2
加味真武汤可能通过减轻近端肾小管上皮细胞氧化应激和线粒体损伤，从而减少氧化应激产物产生和抑制NF-
κ
B信号通路激活引起的炎症因子释放，减轻对心肾组织及功能的损伤，实现延缓慢性肾功能衰竭并发心脏病变进展的目的，且中药组具有量效趋势。
Abstract
Objective
2
By observing the effect of modified Zhenwutang on the expression of superoxide dismutase 1（SOD1）， malondialdehyde（MDA）， advanced oxidation protein product（AOPP）， nuclear factor kappa-B（NF-
κ
B） p65，p-p65，IL-1
β
， TNF-
α
in serum and renal tissue of adenine-induced chronic renal failure rats and the pathology of heart and kidney tissue， the possible mechanism of modified Zhenwutang delaying the progression of chronic renal failure complicated with heart disease was discussed.
Method
2
Fifty SPF male SD rats were divided into normal group 10 and model group 40 according to the random number table method. After one week of adaptive feeding， the experimental chronic renal failure complicated with cardiovascular disease rat model was established by intragastric administration of adenine 150 mg·kg
-1
·d
-1
. After the model was completed， 3 rats in the normal group and the model group were randomly selected to detect whether the model was successful. After successful modeling， the rats in the model group were divided into model group ， modified Zhenwutang low-dose group ， modified Zhenwutang medium-dose group， modified Zhenwutang high-dose group and Benazepril hydrochloride group according to the random number table method， with 6 rats in each group. Drugs were administered once a day for 4 weeks. At the end of the 17
th
week of the experiment， 24-hour urinary total protein（24 h-UTP） and urine creatinine（UCr）were detected. At the end of the 17
th
week， the rats in each group were anesthetized and the abdominal aorta was taken. After centrifugation， the supernatant was taken to detect triglyceride（TG）， total cholesterol（TC）， serum calcium（Ca）， serum potassium， serum phosphate， serum creatinine（Scr）， blood urea nitrogen（BUN）； the expression levels of serum AOPP， IL-1
β
and TNF-
α
were detected by enzyme linked immunosorbent assay（ELISA）. The pathological changes of heart and kidney tissues were observed by hematoxylin-eosin（HE）/Masson method. The ultrastructural changes of proximal renal tubules were observed by transmission electron microscopy . The kidney tissue expressions of SOD1， MDA， AOPP， NF-
κ
B p65，p-p65，IL-1
β
and TNF-
α
were observed by immunohistochemistry. The kidney tissue expression levels of SOD1， NF-
κ
B p65， IL-1
β
and TNF-
α
mRNA were observed by real-time polymerase chain reaction（Real-time PCR）. The kidney tissue expression levels of SOD1， MDA， NF-
κ
B p65 and p-p65 were detected by Western blot.
Result
2
①Compared with the normal group， the experimental rats in the model group showed an increase in 24-hour UTP （
P
<
0.01）and a decrease in UCr（
P
<
0.01）. The experimental rats in the model group showed an increase in Cr， BUN， TG， TC， serum phosphate， and serum potassium（
P
<
0.01）.The levels of AOPP， IL-1
β
and TNF-
α
in serum of rats in the model group were significantly increased（
P
<
0.01）. In the model group， the glomerular balloon space was significantly widened， the renal interstitium was significantly widened with a large number of inflammatory cell infiltration， a large number of renal tubular lumens were blocked by brown deposits， and there were a large number of collagen fiber deposition in the renal interstitium. The collagen fibers around the renal vessels， outside the capsule wall of the renal capsule wall， glomerular basement membrane and renal tubular basement membrane were significantly increased， and the cardiac muscle fibers were significantly thickened. There was a small amount of inflammatory cell infiltration around the blood vessels， and a large number of collagen fibers around the cardiac vessels and between the myocardial cells. In the model group， high-density diamond-shaped needle-like crystals were observed in the proximal renal tubular epithelial cells of rats， with increased lysosomes， mitochondrial proliferation， mitochondrial cristae and dense mitochondrial outer membrane. The left ventricular diastolic wall thickness and systolic wall thickness of the experimental rats in the model group was increased in proximal renal tubular epithelial cells and their nuclei.In the model group， the expression of MDA， AOPP， NF-
κ
B p65，p-p65 IL-1
β
and TNF-
α
in proximal renal tubular epithelial cells was significantly increased（
P
<
0.01）， the expression of p-p65 in the nucleus of proximal renal tubular epithelial cells was significantly increased（
P
<
0.01）， and the expression of SOD1 in proximal renal tubular epithelial cells was significantly decreased（
P
<
0.01）. The kidney tissue expression of NF-
κ
B p65， IL-1
β
and TNF-
α
mRNA in the model group was increased（
P
<
0.01）， and the expression of SOD1 mRNA was decreased（
P
<
0.01）. The kidney tissue expression of SOD1 protein in the model group was significantly decreased（
P
<
0.01）. The kidney tissue expression of MDA， NF-
κ
B p65 and p-p65 protein was increased （
P
<
0.01）. ② Compared with the model group， after the intervention of modified Zhenwutang， 24 h-UTP was decreased （
P
<
0.01）and UCr was increased（
P
<
0.01）. Cr， BUN， TG， TC， serum phosphate， serum potassium was decreased （
P
<
0.01）. Serum AOPP， IL-1
β
and TNF-
α
levels were decreased（
P
<
0.01）. Cardiac and Renal pathological damage was reduced； mitochondrial damage in proximal renal tubules was reduced； the expression of MDA， AOPP， NF-
κ
B p65， IL-1
β
， TNF-
α
in proximal renal tubular epithelial cells was decreased （
P
<
0.01）， the expression of p-p65 in the nucleus of proximal renal tubular epithelial cells was significantly decreased （
P
<
0.01）， and the expression of SOD1 in proximal renal tubular epithelial cells was significantly increased （
P
<
0.01）. The kidney tissue expression of NF-
κ
B p65， IL-1
β
， TNF-
α
mRNA was decreased （
P
<
0.01）， and the expression of SOD1 mRNA was increased（
P
<
0.01）. The kidney tissue expression of SOD1 protein was significantly increased （
P
<
0.01）， and the expression of MDA， NF-
κ
B p65 and p-p65 protein was decreased （
P
<
0.01）. The Chinese medicine group showed a significant dose-effect trend.
Conclusion
2
Modified Zhenwutang may reduce the production of oxidative stress and mitochondrial damage in proximal renal tubular epithelial cells， thereby reducing oxidative stress products and inhibiting the release of inflammatory factors caused by the activation of NF-
κ
B signaling pathway， reducing the damage to heart and kidney tissues and functions， and delaying the progression of chronic renal failure complicated with heart disease， and the traditional Chinese medicine group has a dose-effect trend.
关键词
加味真武汤腺嘌呤慢性肾功能衰竭心脏病变线粒体损伤氧化应激炎症反应
Keywords
modified Zhenwutangadeninechronic renal failureheart diseasemitochondrial damageoxidative stressinflammatory response
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