Ebihara Shin, Tajima Hideaki, Ono Masao
Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan.
Department of Clinical laboratory, National Hospital Organization Mito Medical Center, 280 Sakuranosato, Ibaraki, higashi-ibaraki, Ibaraki, 311-3193, Japan.
Arthritis Res Ther. 2016 Jun 14;18(1):139. doi: 10.1186/s13075-016-1039-5.
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.
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。本研究的目的是评估Nrf2激活剂对人肾小球系膜细胞（HRMCs）的抗炎作用以及对小鼠狼疮性肾炎（LN）发展的影响。
为了在体外评估Nrf2的激活情况，用安全剂量的Nrf2激活剂和泼尼松龙处理HRMCs。使用定量逆转录PCR和酶联免疫吸附测定法测量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。通过单次腹腔注射 pristane在雌性BALB/c小鼠中诱导实验性LN。在注射后20周测量尿白蛋白与肌酐的比值。在实验终点获得的肾脏中评估病理变化以及蛋白质和mRNA表达水平。在注射pristane后开始对这些小鼠口服给予DMF或泼尼松龙。
萝卜硫素和DMF等Nrf2激活剂在HRMCs中显示出抗炎作用，而糖皮质激素（泼尼松龙）显示出部分作用。此外，DMF改善了pristane诱导的LN小鼠的肾脏疾病发展，而糖皮质激素则没有效果。
在肾脏中，Nrf2激活剂比糖皮质激素显示出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。
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