基于SphK1/S1PR2通路探讨肾必宁颗粒对IgA肾病大鼠肾组织的保护作用

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中文摘要：目的:探讨肾必宁颗粒通过鞘氨醇激酶1(sphingosine kinase 1，SphK1)/1-磷酸鞘氨醇受体2(sphingosine 1 phosphate receptor 2，S1PR2)通路改善IgA肾病(IgA nephropathy，IgAN)大鼠肾损伤的作用及机制。方法:将54只健康雄性SD大鼠按照完全随机分组法分为空白组(n=10)、模型组(n=10)、泼尼松组(n=10)、肾必宁低剂量组(n=12)和肾必宁高剂量组(n=12)。除空白组外，其余4组建立IgAN模型，第9周起治疗组灌胃给药，7周后生化检测血肌酐(SCr)、尿素氮(BUN)、谷丙转氨酶(ALT)、血清白蛋白(ALB)、尿红细胞计数及24 h尿蛋白定量(24 h-UTP);苏木素-伊红(HE)染色观察各组大鼠肾组织病理学变化;免疫荧光观察IgA沉积;蛋白免疫印迹(Western blot)法检测SphK1、S1PR2蛋白表达;实时荧光定量PCR法(RT-PCR)检测SphK1、S1PR2 mRNA表达。结果:与空白组比较，模型组大鼠尿红细胞计数、24 h-UTP、SCr、BUN水平均显著升高(P＜0。01或P＜0。05)，ALB水平显著降低(P＜0。01)，ALT水平有所升高，但差异无统计学意义(P＞0。05)，有明显的肾脏病理损伤，免疫荧光可见大量IgA荧光沉积，肾组织SphK1、S1PR2蛋白及mRNA表达水平显著升高(P＜0。01);与模型组比较，泼尼松组、肾低组、肾高组大鼠尿红细胞数、24 h-UTP、BUN水平均明显降低(P＜0。01)，ALB水平显著升高(P＜0。01)，各组ALT水平有所下降，但差异无统计学意义(P＞0。05)，肾低组SCr水平显著降低(P＜0。05)，肾脏病理有不同程度改善，IgA荧光沉积可见不同程度减少，肾组织SphK1、S1PR2蛋白及mRNA表达水平明显下降(P＜0。01)。结论:肾必宁颗粒可能通过抑制SphK1/S1PR2通路来降低IgAN大鼠尿蛋白，减轻血尿并改善肾功能，从而起到保护肾脏、防治肾损害的作用。

外文标题：Protective effect of Shenbining Granule on renal tissue of IgA nephropathy rats based upon SphK1/S1PR2 pathway

外文摘要：OBJECTIVE To explore the effect and mechanism of Shenbining Granule(SG)on renal injury in rats with IgA nephropathy(IgAN)through sphingosine kinase 1(SphK1)/sphingosine 1 phosphate receptor 2(S1PR2)pathway.METHODS A total of 54 healthy male Sprague-Dawley rats were randomized into 5 groups of blank(n=10),model(n=10),prednisone(n=10),low-dose SG(n=12)and high-dose SG(n=12).Except for blank group,IgAN model was established in the other four groups.Treatment groups received intragastric dosing from Week 9.After 7 weeks,serum creatinine(SCr),blood urea nitrogen(BUN),alanine aminotransferase(ALT),serum albumin(ALB),urinary erythrocyte count and 24-hour urinary protein quantity(24 h-UTP)were measured.Renal pathological changes were observed by hematoxylin-eosin(HE)stain and IgA deposition was detected by immunofluorescence.The protein expressions of SphK1 and S1PR2 were examined by Western blot and the expressions of SphK1 and S1PR2 mRNA by real-time fluorescent quantitative polymerase chain reaction(RT-PCR).RESULTS As compared with blank group,urinary erythrocyte count,the levels of 24 h-UTP,SCr and BUN spiked signifi-cantly in model group(P＜0.01 or P＜0.05).The level of ALB dropped obviously(P＜0.01)while the level of ALT rose.However,no significant difference existed between model and blank groups(P＞0.05).There was obvious renal pathological injury.Massive IgA deposition could be detected by immunofluorescence.The expression levels of SphK1,S1PR2 protein and mRNA jumped sharply in renal tissue(P＜0.01).As compared with model group,urinary erythrocyte count,the levels of 24 h-UTP and BUN declined obviously in prednisone,low-dose SG and high-dose SG groups(P＜0.01),ALB level became mark-edly elevated(P＜0.01)while ALT level declined.The differences were not statistically significant(P＞0.05).SCr level declined markedly in low-dose SG group(P＜0.05).Renal pathology improved and IgA fluorescent deposition diminished.The expressions of SphK1,S1PR2 protein and mRNA dropped significantly in renal tissue(P＜0.01).CONCLUSION SG may lower urinary protein,lessen hematuria and improve renal function in IgAN rats through an inhibition of SphK1/S1PR2 pathway.Thus it protects kidney and prevents renal damage.

外文关键词：

Shenbining GranuleIgA nephropathysphingosine kinase 1/sphingosine 1 phosphate receptor 2 pathwayrenal injury

作者：

姜浩然、宋纯东、段凤阳、王宁丽、郭婷、张博、张霞、丁樱、任献青、翟文生

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作者单位：

河南中医药大学第一附属医院儿科医院,河南郑州 450000

河南中医药大学儿科医学院,河南郑州 450046

关键词：

肾必宁颗粒 IgA肾病鞘氨醇激酶1/1-磷酸鞘氨醇受体2信号通路肾损伤

基金：

国家自然科学基金面上项目河南省中医药学科领军人才项目河南省卫生健康委国家中医临床研究基地科研专项河南省中医药科学研究重大专项

项目编号：

82074493豫卫中医函20218号2022JDZX0032023ZYZD02

出版年：

2024

DOI：

10.13286/j.1001-5213.2024.11.02

中国医院药学杂志

中国药学会

中国医院药学杂志

CSTPCD北大核心

影响因子：1.198

ISSN：1001-5213

年,卷(期)：2024.44(11)

参考文献量27