Morath Christian, Dechow Claudius, Lehrke Ingo, Haxsen Volker, Waldherr Rüdiger, Floege Jürgen, Ritz Eberhard, Wagner Jürgen
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Department of Nephrology, University of Aachen, Aachen, Germany.
J Am Soc Nephrol. 2001 Nov;12(11):2300-2309. doi: 10.1681/ASN.V12112300.
Transforming growth factor-beta1 (TGF-beta 1) overexpression plays a key role in the glomerular accumulation of extracellular matrix proteins in renal disease. Retinoids have previously been shown to significantly limit glomerular damage in rat experimental glomerulonephritis. Therefore, the effects of all-trans retinoic acid and isotretinoin on the components of the TGF-beta system and extracellular matrix proteins in anti-Thy1.1-nephritis (Thy-GN) were investigated. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of 10 mg/kg body wt all-trans retinoic acid or 40 mg/kg body wt isotretinoin (n = 9 per group) either with a pretreatment (day -2 through 8) or posttreatment protocol (day +3 through 8), i.e., starting before or after induction of Thy-GN, respectively. Urinary TGF-beta 1 excretion was 60% lower in all-trans retinoic acid-treated animals with Thy-GN (P < 0.025). The increase of cortical TGF-beta 1 gene expression in Thy-GN rats was significantly attenuated with all-trans retinoic acid and even more with isotretinoin treatment as compared with untreated animals (P < 0.025). Cortical expression of TGF receptor II, but not receptor I gene expression, was significantly lower in animals treated with all-trans retinoic acid or isotretinoin (P < 0.05). In all-trans retinoic acid-treated animals with Thy-GN, the increase of glomerular TGF-beta 1 protein (P < 0.008) and TGF-beta 1 (P < 0.025) and TGF receptor II mRNA (P < 0.015) was significantly less. Immunohistochemistry revealed less glomerular staining for TGF-beta 1 and TGF receptor II in the presence of all-trans retinoic acid. TGF-beta 1 immunostaining was not restricted to monocytes and macrophages, as indicated by double-staining. Glomerular staining for collagen IV and collagen III was less in animals treated with isotretinoin (P < 0.02 for both) in contrast to all-trans retinoic acid, whereas fibronectin remained unchanged. It was concluded that the beneficial effects of retinoids on glomerular damage are presumably due to a marked reduction in renal TGF-beta 1 and TGF receptor II expression.
转化生长因子-β1（TGF-β1）的过表达在肾脏疾病中细胞外基质蛋白的肾小球积聚过程中起关键作用。此前已表明类视黄醇可显著限制大鼠实验性肾小球肾炎中的肾小球损伤。因此，研究了全反式维甲酸和异维甲酸对抗Thy1.1肾炎（Thy-GN）中TGF-β系统成分和细胞外基质蛋白的影响。将注射赋形剂的对照大鼠与每日皮下注射10mg/kg体重全反式维甲酸或40mg/kg体重异维甲酸的大鼠（每组n = 9）进行比较，给药方案分为预处理（第-2天至第8天）或后处理方案（第+3天至第8天），即分别在诱导Thy-GN之前或之后开始给药。患有Thy-GN的全反式维甲酸处理动物的尿TGF-β1排泄量降低了60%（P < 0.025）。与未处理动物相比，全反式维甲酸显著减弱了Thy-GN大鼠皮质TGF-β1基因表达的增加，而异维甲酸处理的减弱作用更明显（P < 0.025）。全反式维甲酸或异维甲酸处理的动物中，TGF受体II的皮质表达显著降低，但受体I基因表达未降低（P < 0.05）。在患有Thy-GN的全反式维甲酸处理动物中，肾小球TGF-β1蛋白（P < 0.008）、TGF-β1（P < 0.025）和TGF受体II mRNA（P < 0.015）的增加显著减少。免疫组织化学显示，在存在全反式维甲酸的情况下，TGF-β1和TGF受体II的肾小球染色减少。双重染色表明，TGF-β1免疫染色不限于单核细胞和巨噬细胞。与全反式维甲酸相反，异维甲酸处理的动物中IV型胶原和III型胶原的肾小球染色减少（两者均P < 0.02），而纤连蛋白保持不变。得出的结论是，类视黄醇对肾小球损伤的有益作用可能归因于肾脏TGF-β1和TGF受体II表达的显著降低。
