HSP 90在原发性肾病综合征发生和治疗中的意义

Significance of Heat Shock Protein 90 in Glucorticoid Resistance in Idiopathic Nephrotic Syndrome

【目的】热休克蛋白90(HSP90)是糖皮质激素受体(GR)的伴侣蛋白,本研究探讨HSP90在原发性肾病综合征(INS)发生和糖皮质激素(GC)在治疗中的作用本质。【方法】以INS患者和GC敏感、抵抗的细胞株为研究对象,分析其HSP90、GR表达水平及HSP90的亚细胞分布;并采用HSP90特异性阻断剂研究HSP90对GC反应性的影响。【结果】与对照组比较,INS患者HSP90mRNA表达水平明显增高;而且INS患者中GC抵抗组HSP90mRNA表达显著高于GC敏感组(P<0.05)。深入研究发现对照组的HSP90主要分布在细胞浆中,核内仅有微量分布;INS患者的HSP90表达有所增加,并且GC抵抗组与敏感组比较,HSP90明显趋向细胞核内分布(P<0.001)。用HSP90特异性阻断剂后发现激素敏感细胞株的GC反应性也显著下降(P<0.01)。【结论】研究表明HSP90的异常表达及亚细胞分布变化可能是导致GC抵抗的重要机制,其一方面可能影响内源性GC对神经-内分泌-免疫网络的功能调节,进而影响机体免疫内环境的稳定,从而参与INS等免疫损伤性疾病的发病;另一方面则可能干预患者对外源性GC的治疗反应,影响临床疗效。

[Objective] Heat shock protein 90 （HSP90） is the chaperon protein of the glucocorticoid （GC） receptor, which is supposed to be the key factor of GC response. Thus, this study was designed to define the mechanisms of GC-resistance in the idiopathic nephrotic syndrome （INS） related to HSP90. [Methods] The INS patients and the cell lines with different GC response were included in the present study. RT-PCR and the confocal immunofluorescence test were performed to investigate the expression and the subeellular locahzation of the GC receptor and HSP90. [Results] The level of HSP90 mRNA expression in the INS patients was significandy higher than that in healthy control, and HSP90 expression in the GC-resistant INS patients was higher than that in the GC-sensitive INS patients. The distribution of HSP90 in the GC-resistant INS group was greater in the nuclei than that of the GC-sensitive INS group. When the function of HsPg0 was blocked by the HSP90 specific inhibitor, GC sensitivity of the GC-sensitive cells decreased remarkably. [Conclusion ] These results indicate that HSP90 plays a vital role in GC-response. The abnormality in the mRNA level and subcellular distribution of HSP90 in GC- resistant INS patients may be etiologic significant in endogenous /synthetic GC resistance. It may disturb immunoendocrine regulation via endogenous GC and immune homeostasis, thus be involved in the occurrence of the immune-mediated diseases; it may also influence patient＂ s response to synthetic GC treatment, and result in treatment failure.