Nuclear factor erythroid 2-related factor 2 is a critical target for the treatment of glucocorticoid-resistant lupus nephritis.
Nuclear factor erythroid 2-related factor 2 is a critical target for the treatment of glucocorticoid-resistant lupus nephritis.
复制标题
DOI：
10.1186/s13075-016-1039-5
复制
发表时间：
2016-06-14
影响因子：
4.9
通讯作者：
Ono M
中科院分区：
文献类型：
--
作者：
Ebihara S;Tajima H;Ono M
富马酸二甲酯（DMF）是一种核因子红细胞2相关因子2 （Nrf2）激活剂，已被证明对多发性硬化症的全身治疗有效。本研究旨在评价Nrf2激活剂对人肾系膜细胞（HRMCs）的抗炎作用和小鼠狼疮性肾炎（LN）的发生。为了评估Nrf2的体外激活，hrmc接受安全剂量的Nrf2激活剂和强的松龙治疗。采用定量反转录PCR和酶联免疫吸附法检测Nrf2及其靶基因的表达水平。通过测量肿瘤坏死因子α诱导的细胞因子分泌来评估这些化合物的抗炎作用。雌性BALB/c小鼠经单次腹腔注射普利斯坦诱导实验性LN。注射后20周测定尿白蛋白与肌酐比值。在实验结束时评估肾脏的病理变化以及蛋白质和mRNA的表达水平。在普利斯坦注射后，对这些小鼠口服DMF或强的松龙。Nrf2激活剂如萝卜硫素和DMF在hrmc中显示抗炎作用，而糖皮质激素（强的松龙）显示部分作用。此外，DMF改善了前列腺素诱导的LN小鼠肾脏疾病的发展，而糖皮质激素没有作用。Nrf2激活剂在肾脏中表现出比糖皮质激素更强的抗炎和器官保护作用。因此，Nrf2激活剂是人类糖皮质激素抵抗性LN的潜在治疗靶点。
Dimethyl fumarate (DMF), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, has been proven effective for the systemic treatment of multiple sclerosis. The aim of this study is to evaluate the anti-inflammatory effects of Nrf2 activators on human renal mesangial cells (HRMCs) and the development of lupus nephritis (LN) in mice. To assess Nrf2 activation in vitro, HRMCs were treated with safe doses of Nrf2 activators and prednisolone. The expression levels of Nrf2 and its target genes were measured using quantitative reverse transcription PCR and enzyme-linked immunosorbent assay. The anti-inflammatory effects of these compounds were assessed by measuring tumor necrosis factor alpha-induced cytokine secretion. Experimental LN was induced in female BALB/c mice by a single intraperitoneal injection of pristane. The urine albumin-to-creatinine ratio was measured at 20 weeks after injection. Pathological changes as well as protein and mRNA expression levels were assessed in the kidney obtained at the experimental end point. Oral administration of DMF or prednisolone to these mice was initiated after pristane injection. Nrf2 activators such as sulforaphane and DMF showed anti-inflammatory effects in HRMCs, whereas glucocorticoid (prednisolone) showed partial effects. Moreover, DMF ameliorated the development of kidney diseases in pristane-induced LN mice, whereas glucocorticoid had no effect. Nrf2 activators showed stronger anti-inflammatory and organ-protective effects than glucocorticoid in the kidney. Thus, Nrf2 activators are potential therapeutic targets in glucocorticoid-resistant LN in humans.