HMGB1在狼疮性肾炎肾小球细胞外基质沉积中的作用及其可能机制

HMGB1 Mediate Extracellular Matrix Deposition of Glomerular Mesangial Cell of Lupus Nephritis through Combining with RAGE

狼疮性肾炎(lupus nephritis,LN)的病理改变多种多样,硬化性肾小球肾炎是多数LN患者的终末阶段,因此,该研究探讨了肾小球硬化的原因及机制。该研究通过免疫组化技术检测发现,与癌旁远端正常组织相比,LN肾组织晚期糖基化终产物受体(receptor for advanced glycation end products,RAGE)与IV型胶原蛋白(collagen IV,Col IV)的表达水平均明显上调且二者呈明显正相关;ELISA技术检测结果发现,甘草酸及Box A均可抑制由狼疮性肾炎患者置换血浆所诱导的人系膜细胞培养上清中FN蛋白表达的上调;Western blot及IP检测显示,高迁移率组蛋白B1(high mobility group box 1,HMGB1)可与HMC表面的RAGE结合并上调其表达水平。综上所述,研究者推测,HMGB1可能先与系膜细胞表面的RAGE结合,继而诱导系膜细胞细胞外基质沉积,从而参与LN肾损伤的发生。

Lupus nephritis（LN） is the most frequent visceral complication of SLE, accounting for an increased morbidity, including end stage renal disease and mortality. Above all, it is an important significance to explore the mechanism of LN and look for personalized treatment options. Our previous researches had revealed that HMGB1 was significantly increased in renal tissue and correlated with the renal glomeruli proliferation in MRL/Faslpr mice. In this study, we want to further explore the realtionship between HMGB1 and extracellular matrix deposition of renal glomeruli with lupus nephritis. Plasmas from patients with LN and glycyrrhizinic acid,a specific inhibitor of HMGB1, were used to infer the role of HMGB1 in extracellular matrix deposition of HMC;renopuncture tissues were used to revealed the correlationship of RAGE and Collagen IV; human recombinant HisHMGB1 and Box A, a specific inhibitor of RAGE, were used to infer the mechanism of HMGB1 in extracellular matrix deposition of HMC. The ELISA result showed that compared with control group, the expression of FNprotein in LN palsma group was increased and the secretion of FN in Gly＋LN palsma group was downregulated compared with LN palsma group, indicated that the Gly blocked the FN secretion induced by plasma from patients with LN; the secretion of FN in HMC of Box A＋His-HMGB1 group was decreased compared with His-HMGB1 group, which showed that Box A blocked the FN secretion induced by His-HMGB1. The immunohistochemical result showed that the expression of RAGE protein in renopuncture tissues of patients with LN was upregulated and showed statistic correlation with the expression of Collagen IV. The Western blot result showed that the expression of RAGE protein in HMC was upregulated by His-HMGB1 compared with control group. The IP result revealed that the combine of RAGE and His-HMGB1 protein in HMC. In conclusion, HMGB1 mediate the extracellular matrix deposition of glomerular mesangial cell of LN through combining with RAGE.