剪接因子SRp40调控糖皮质激素受体α/β的表达及其对肾病综合征患者糖皮质激素疗效的影响

中国临床药理学与治疗学

剪接因子SRp40调控糖皮质激素受体α/β的表达及其对肾病综合征患者糖皮质激素疗效的影响

张军¹，谢艳云¹，李智²，陶立坚¹

¹中南大学湘雅医院肾内科，长沙 410008，湖南； ² 中南大学湘雅医院临床药理研究所，长沙 410008，湖南

出版日期:2017-05-26 发布日期:2017-05-27
作者简介:张军，男，博士研究生，副主任医师，主要从事肾脏病的基础与临床研究。 Tel:0731-84328888 E-mail:zhangjunlj@126.com

Effects of splicing factor SRp40 on the expression of GRα/β mRNA and on glucocorticoid therapy for nephrotic syndrome

ZHANG Jun¹, XIE Yanyun ¹, LI Zhi ², TAO Lijian ¹

¹ Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; ² Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China

Online:2017-05-26 Published:2017-05-27

摘要/Abstract

摘要：

目的: 明确肾病综合征患者(NS)外周血单个核细胞(PBMC)糖皮质激素受体α和β(GRα和GRβ)与剪接因子SRp40mRNA的表达水平，探讨剪接因子对糖皮质激素受体premRNA可变剪接的调控作用，同时查明糖皮质激素受体亚型的差异表达对肾病综合征患者糖皮质激素治疗效应之间的影响。方法: 临床收集健康志愿者20例、NS患者46例，根据患者对糖皮质激素（GC）治疗效应，将NS患者分为GC敏感组（24例）和GC抵抗组（22例）。收集受试者外周静脉血6 mL，采用实时定量PCR(Quantitative Realtime PCR)方法检测健康志愿者及GC敏感组与GC抵抗组患者治疗前后PBMC中GRα、GRβ及剪接因子SRp40的mRNA表达量；分析GR及SRp变化的相关性及其对NS临床疗效的影响。结果: NS患者与健康对照组PBMC中均有GRα、GRβ mRNA表达，其中GRα为主要GR受体亚型；GRα、GRβ mRNA的表达水平在GC抵抗组与GC敏感组未见显著差异，但GC抵抗组SRp40的mRNA表达量明显高于GC敏感组及正常对照组(P=0.035)；糖皮质激素治疗后GC抵抗组GRβ的表达显著增加（P<0.001），但GRα mRNA表达量在两组患者间无统计学意义；线性回归分析显示GRβ mRNA表达量与SRp40 mRNA呈显著正相关（P=0.006）。结论: SRp40高表达可能通过调控可变剪接、诱导GRβ高表达，参与NS患者GC抵抗的发生，NS患者外周血PBMC中GRβ及SRp40的表达水平可能成为NS患者激素敏感性的预测因子。

关键词: 肾病综合征, 糖皮质激素抵抗, 糖皮质激素受体, α/β亚型, 剪接因子SRp40

Abstract:

AIM: To determine the expression of glucocorticoid (GC) receptor GRα/GRβ and splicing factor SRp40 in peripheral blood mono-nuclear cells (PBMC) of nephrotic syndrome (NS) patients so as to investigate the regulating effect of splicing factor on GC and differential expression of GC receptor on GC therapy. METHODS: Twenty healthy volunteers and 46 NS patients were included. The NS patients were divided into GC-sensitive (n=24) and GC-resistant group (n=22) according to the response to GC therapy. Quantitative Real-time PCR was performed to investigate the mRNA expression of GRα/GRβ and SRp40 in healthy volunteers and NS patients before and after glucocorticoid treatment. The expression level of GRα/GRβ and SRp40 mRNA were compared between groups and analyzed to assess the relevance of GC receptor and slicing factor and their effect on clinical outcomes. RESULTS: The expression of GRα and GRβ mRNA were detected both in control and NS patients with the GRα as the domination sub-type, and no significant difference was observed between GC-sensitive and GC-resistant group. While the expression of SRp40 mRNA on PBMC in GC-resistant group was significantly higher than that in GC-sensitive group and in health control (P=0.035). The expression level of GR in GC-resistant group was significantly increased after GC treatment （P<0.001）, but no significant difference of the GRα mRNA expression was observed between NS groups. And the expression of GRβ mRNA level was found positively associated with SRp40 level through linear regression method. CONCLUSION:The over expression of SRp40 can induce the over expression of GRβ mRNA through modulating alternative splicing, which may be a risk factor in the resistance of GC in NS patients. And levels of GRβ and SRp40 mRNA may be predictors for GC resistance in NS patients.

Key words: nephrotic syndrome, glucocorticoid resistance, glucocorticoid receptor α/β, splicing factor SRp40

中图分类号:

R692

张军，谢艳云，李智，陶立坚. 剪接因子SRp40调控糖皮质激素受体α/β的表达及其对肾病综合征患者糖皮质激素疗效的影响[J]. 中国临床药理学与治疗学.

ZHANG Jun, XIE Yanyun, LI Zhi, TAO Lijian. Effects of splicing factor SRp40 on the expression of GRα/β mRNA and on glucocorticoid therapy for nephrotic syndrome[J]. Chinese Journal of Clinical Pharmacology and Therapeutics.

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