Rodríguez-Peña Ana, Eleno Nélida, Düwell Anette, Arévalo Miguel, Pérez-Barriocanal Fernando, Flores Olga, Docherty Neil, Bernabeu Carmelo, Letarte Michelle, López-Novoa José M
Instituto Reina Sofía de Investigación Nefrológica, Departamento de Fisiología & Farmacología, Universidad de Salamanca, Salamanca, Spain.
Hypertension. 2002 Nov;40(5):713-20. doi: 10.1161/01.hyp.0000037429.73954.27.
The goal of the present study was to evaluate the role of endoglin, a transforming growth factor-beta1 (TGF-beta1) accessory receptor, in the pathogenesis of renal fibrosis. This was achieved by testing a model of tubulo-interstitial fibrosis induced by unilateral ureteral obstruction in endoglin heterozygous (Eng(+/-)) mice. Northern and Western blot analysis revealed that endoglin expression in kidneys of these mice was significantly reduced compared with Eng(+/+) littermates. Pronounced interstitial fibrosis induced by ureteral obstruction was confirmed histologically by Masson's trichromic staining and by increased immunostaining for fibronectin and laminin without significant differences between Eng(+/-) and Eng(+/+) mice. Ureteral obstruction induced significant increases in alpha2(I) and alpha1(IV) collagen, fibronectin, and TGF-beta1 mRNA levels, as well as in total kidney collagen but changes were similar in Eng(+/-) and Eng(+/+) mouse kidneys. Ureteral obstruction also induced a 2-fold increase in endoglin mRNA levels in both Eng(+/+) mice and Eng(+/-) mice, which was confirmed by Western blot analysis. Thus, the present study provides clear evidence that endoglin is upregulated in the kidneys of mice with interstitial fibrosis induced by unilateral ureteral ligation. However, Eng(+/-) mice do not show any changes in the severity of renal disease induced in this model when compared with normal mice, suggesting that the absolute level of endoglin is not critical for the effects of TGF-beta1 in the renal fibrosis process.
本研究的目的是评估内皮糖蛋白（一种转化生长因子-β1（TGF-β1）辅助受体）在肾纤维化发病机制中的作用。通过在杂合型内皮糖蛋白（Eng(+/-)）小鼠中测试单侧输尿管梗阻诱导的肾小管间质纤维化模型来实现这一目的。Northern印迹和Western印迹分析显示，与Eng(+/+)同窝小鼠相比，这些小鼠肾脏中的内皮糖蛋白表达显著降低。输尿管梗阻诱导的明显间质纤维化通过Masson三色染色以及纤连蛋白和层粘连蛋白免疫染色增加在组织学上得到证实，Eng(+/-)小鼠和Eng(+/+)小鼠之间无显著差异。输尿管梗阻导致α2（I）和α1（IV）胶原、纤连蛋白以及TGF-β1 mRNA水平显著升高，同时肾脏总胶原含量也增加，但Eng(+/-)小鼠和Eng(+/+)小鼠肾脏中的变化相似。输尿管梗阻还导致Eng(+/+)小鼠和Eng(+/-)小鼠的内皮糖蛋白mRNA水平均增加两倍，这通过Western印迹分析得到证实。因此，本研究提供了明确证据，表明在单侧输尿管结扎诱导的间质纤维化小鼠肾脏中内皮糖蛋白上调。然而，与正常小鼠相比，Eng(+/-)小鼠在该模型中诱导的肾脏疾病严重程度未显示任何变化，这表明内皮糖蛋白的绝对水平对于TGF-β1在肾纤维化过程中的作用并不关键。
