Retinoid receptor-specific agonists alleviate experimental glomerulonephritis
Retinoid receptor-specific agonists alleviate experimental glomerulonephritis
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DOI：
10.1152/ajprenal.00026.2001
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发表时间：
2002-04-01
影响因子：
4.2
通讯作者：
Wagner, J
中科院分区：
文献类型：
--
作者：
Lehrke, I;Schaier, M;Wagner, J
维甲酸是一种有效的抗增殖和抗炎化合物。我们先前证明了天然的全反式维甲酸(RA)和13-顺式维甲酸(13-cis RA)有效地保护了系膜增生性肾小球肾炎大鼠的肾脏结构和功能。我们检测合成的维甲酸受体特异性激动剂的作用，1)确定在该模型中常见的和受体亚型特异性的通路，2)表征维甲酸对肾脏内皮素(ET)系统的影响。分别于诱导抗Thy1.1肾炎后7d，每日皮下注射视黄醇A受体激动剂(Ro-137410)、视黄醇X受体激动剂(Ro-257386)和复合抗激活蛋白-1活性视黄酸受体激动剂(n=7~9/组)。不同维甲酸降低正常大鼠和肾病大鼠肾小球ET-1及ET A、B受体基因表达，疗效相当。肾小球c-Fos和GATA-2mRNA表达水平的降低表明ET表达所需的转录因子下调。不同的维甲酸对肾小球毛细血管闭塞积分、肾小球细胞总数和肾小球浸润性巨噬细胞计数的作用相似。它们在使血压正常化(Ro-257386和GT；BMS-453和GT；Arotinid)、蛋白尿(Ro-453和Gt；Ro-257386和Gt；Arotinid)和肌酐清除(Arotinid&Gt；BMS-453和GT；Ro-257386)方面存在差异。没有观察到毒性的迹象。我们得出结论，所有不同亚型特异性的维甲酸激动剂在减少肾损伤和系膜细胞增殖方面都是非常有效的。视黄醇X和A受体特异性通路明显参与了抗增殖、抗炎和抗ET的作用。进一步的研究表明，维甲酸激动剂在炎症性肾脏疾病中的潜在用途。
Retinoids are potent antiproliferative and anti-inflammatory compounds. We previously demonstrated that the natural pan-agonists all-trans retinoic acid (RA) and 13-cis RA efficiently preserve renal structure and function in rat mesangioproliferative glomerulonephritis. We examine effects of synthetic retinoid receptor-specific agonists 1) to identify common and receptor subtype-specific pathways in this model and 2) to characterize effects of retinoids on the renal endothelin (ET) system. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of agonists specific for retinoid A (Ro-137410) and retinoid X (Ro-257386) receptors and the complex anti-activator protein-1 active retinoid BMS-453 7 days after induction of anti-Thy1.1 nephritis (n = 7-9/group). The different retinoids lowered glomerular ET-1 and ET type A and B receptor gene expression in control and nephritic rats with comparable efficacy. Reduction of glomerular c-Fos and GATA-2 mRNA expression levels suggests downregulation of transcription factors required for ET expression. The different retinoids were similar in their action on the glomerular capillary occlusion score, number of total glomerular cells, and glomerular infiltrating macrophage count. They differed in their ability to normalize blood pressure (Ro-257386 > BMS-453 > arotinoid), albuminuria (BMS-453 > Ro-257386 > arotinoid), and creatinine clearance (arotinoid > BMS-453 > Ro-257386). No signs of toxicity were observed. We conclude that all retinoid agonists with different subtype specificity are highly efficient in reducing renal damage and proliferation of mesangial cells. Retinoid X and A receptor-specific pathways are apparently involved in the antiproliferative, anti-inflammatory, and anti-ET action. Further studies are indicated to define the potential use of retinoid agonists in inflammatory renal disease.