Retinoic acid treatment protects MRL/lpr lupus mice from the development of glomerular disease
Retinoic acid treatment protects MRL/lpr lupus mice from the development of glomerular disease
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DOI：
10.1111/j.1523-1755.2004.00850.x
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发表时间：
2004-09-01
影响因子：
19.6
通讯作者：
Schlöndorff, D
中科院分区：
文献类型：
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作者：
de Lema, GP;Lucio-Cazaña, FJ;Schlöndorff, D
背景。视黄酸（tRA）是维生素A的活性代谢物，具有有效的抗炎特性。我们分析了tRA对MRL/lpr小鼠狼疮性肾炎发展的影响。MRL/lpr小鼠从8 ~ 14周开始接受添加载药或tRA（每日10 mg/kg）的饲料，直至牺牲。MRL/wt小鼠作为额外的对照。与对照组相比，经tra治疗的MRL/lpr小鼠淋巴腺病和脾肿大减少。治疗将蛋白尿减少到基本水平。小鼠血浆IgG和抗dna抗体均显著升高。给药小鼠出现特征性肾损害。相反，经tra治疗的小鼠肾小球组织学几乎正常，毛细血管内细胞增殖明显减少。经tRA治疗后，肾小球和间质内的t细胞和巨噬细胞浸润量较对照组减少。尽管如此，两组的免疫复合物和补体沉积具有可比性。将T细胞从载体处理过的MRL/lpr小鼠过代转移到tra处理过的MRL/lpr小鼠中，没有引起肾脏病变或蛋白尿。tRA治疗的这些有益效果与肾脏趋化因子和炎症细胞因子的表达减少有关。令人惊讶的是，tra治疗小鼠的肾转化生长因子- β (tgf - β) mRNA水平升高，可能表明tgf - β在狼疮模型中起抗炎信号的作用。tRA治疗可减少MRL/lpr小鼠的淋巴细胞增殖和肾小球肾炎。尽管抗dna滴度和肾小球免疫复合物沉积不变，但这种情况仍会发生，并且不能通过肾脏MRL/lpr小鼠的t细胞转移来克服。
Background. Retinoic acid (tRA) is an active metabolite of vitamin A with potent anti-inflammatory properties. We analyzed the effects of tRA on the development of lupus nephritis in MRL/lpr mice.Methods. MRL/lpr mice received chow supplemented with vehicle or tRA (daily 10 mg/kg) from 8 to 14 weeks until their sacrifice. MRL/wt mice served as an additional control.Results. tRA-treated MRL/lpr mice showed reduced lymphoadenopathy and splenomegaly as compared to vehicle-treated controls. Treatment reduced proteinuria to almost basal levels. Plasma IgG and anti-DNA antibodies increased comparably in both vehicle and tRA-treated mice. Vehicle-treated mice showed characteristic renal lesions. In contrast tRA-treated mice showed almost normal glomerular histology with a pronounced reduction in endocapillary cell proliferation. T-cell and macrophage infiltrates were reduced after tRA treatment within glomeruli and interstitium as compared to vehicle-treated animals. In spite of this, immune complex and complement deposition were comparable in both groups. Adoptively transferred T cells from vehicle-treated to tRA-treated MRL/lpr mice did not induce renal lesions or proteinuria. These beneficial effects of tRA treatment were associated with reduced renal expression of chemokines and inflammatory cytokines. Surprisingly, renal transforming growth factor-beta (TGF-beta) mRNA levels of tRA-treated mice were elevated, possibly indicating that TGF-beta acts as an anti-inflammatory signal in this lupus model.Conclusion. tRA treatment reduces lymphoproliferation and glomerulonephritis in MRL/lpr mice. This occurs in spite of unaltered anti-DNA titers and glomerular immune complex deposition, and cannot be overcome by T-cell transfer from nephritic MRL/lpr mice.