Docherty Neil G, López-Novoa José M, Arevalo Miguel, Düwel Annette, Rodriguez-Peña Ana, Pérez-Barriocanal Fernando, Bernabeu Carmelo, Eleno Nélida
Departamento de Fisiología y Farmacología, Edificio Departamental, Campus Miguel de Unamuno 37007, Salamanca, Spain.
Nephrol Dial Transplant. 2006 Aug;21(8):2106-19. doi: 10.1093/ndt/gfl179. Epub 2006 Jun 4.
Renal ischaemia-reperfusion (I-R) can cause acute tubular necrosis and chronic renal deterioration. Endoglin, an accessory receptor for Transforming Growth Factor-beta1 (TGF-beta1), is expressed on activated endothelium during macrophage maturation and implicated in the control of fibrosis, angiogenesis and inflammation.
Endoglin expression was monitored over 14 days after renal I-R in rats. As endoglin-null mice are not viable, the role of endoglin in I-R was studied by comparing renal I-R injury in haploinsufficient mice (Eng(+/-)) and their wild-type littermates (Eng(+/+)). Renal function, morphology and molecular markers of acute renal injury and inflammation were compared.
Endoglin mRNA up-regulation in the post-ischaemic kidneys of rats occurred at 12 h after I-R; endoglin protein levels were elevated throughout the study period. Expression was initially localized to the vascular endothelium, then extended to fibrotic and inflamed areas of the interstitium. Two days after I-R, plasma creatinine elevation and acute tubular necrosis were less marked in Eng(+/-) than in Eng(+/+) mice. Significant up-regulation of endoglin protein was found only in the post-ischaemic kidneys of Eng(+/+) mice and coincided with an increased mRNA expression of the TGF-beta1 and collagen IV (alpha1) chain genes. Significant increases in vascular cell adhesion molecule-1 (VCAM-1) and inducible nitric oxide synthase (iNOS) expression, nitrosative stress, myeloperoxidase activity and CD68 staining for macrophages were evident in post-ischaemic kidneys of Eng(+/+), but not Eng(+/-) mice, suggesting that impaired endothelial activation and macrophage maturation may account for the reduced injury in post-ischaemic kidneys of Eng(+/-) mice.
Endoglin is up-regulated in the post-ischaemic kidney and endoglin-haploinsufficient mice are protected from renal I-R injury. Endoglin may play a primary role in promoting inflammatory responses following renal I-R.
肾缺血再灌注（I-R）可导致急性肾小管坏死和慢性肾功能恶化。内皮糖蛋白是转化生长因子-β1（TGF-β1）的辅助受体，在巨噬细胞成熟过程中在内皮细胞活化时表达，并参与纤维化、血管生成和炎症的调控。
监测大鼠肾I-R后14天内内皮糖蛋白的表达情况。由于内皮糖蛋白基因敲除小鼠无法存活，通过比较单倍体不足小鼠（Eng(+/-)）及其野生型同窝小鼠（Eng(+/+)）的肾I-R损伤，研究内皮糖蛋白在I-R中的作用。比较肾功能、形态以及急性肾损伤和炎症的分子标志物。
大鼠缺血后肾脏中内皮糖蛋白mRNA在I-R后12小时上调；在整个研究期间内皮糖蛋白蛋白水平升高。表达最初定位于血管内皮，随后扩展到间质的纤维化和炎症区域。I-R后两天，Eng(+/-)小鼠的血浆肌酐升高和急性肾小管坏死比Eng(+/+)小鼠轻。仅在Eng(+/+)小鼠缺血后肾脏中发现内皮糖蛋白蛋白显著上调，且与TGF-β1和胶原蛋白IV（α1）链基因的mRNA表达增加一致。在Eng(+/+)小鼠缺血后肾脏中，血管细胞黏附分子-1（VCAM-1）和诱导型一氧化氮合酶（iNOS）表达、亚硝化应激、髓过氧化物酶活性以及巨噬细胞的CD68染色显著增加，而Eng(+/-)小鼠则未出现，这表明内皮细胞活化和巨噬细胞成熟受损可能是Eng(+/-)小鼠缺血后肾脏损伤减轻的原因。
内皮糖蛋白在缺血后肾脏中上调，内皮糖蛋白单倍体不足的小鼠可免受肾I-R损伤。内皮糖蛋白可能在促进肾I-R后的炎症反应中起主要作用。
