Fukuda K, Yanagida T, Okuda S, Tamaki K, Ando T, Fujishima M
Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Kidney Int. 1996 May;49(5):1320-9. doi: 10.1038/ki.1996.188.
Recent studies have revealed that endothelin-1 (ET-1) is a potent mitogen for mesangial cells in vitro. To determine whether ET-1 exerts the mitogenic action on mesangial cells in vivo, we examined the glomerular expression of ET-1 and its receptors in a rat model of mesangial proliferative glomerulonephritis and assessed the effect of a specific endothelin A (ET(A)) receptor antagonist, FR139317, on mesangial cell proliferation in this model. The levels of preproET-1 mRNA expression and ET-1 protein production in glomeruli increased markedly on days 4 and 7 after disease induction, and the levels changed in concordance with the glomerular cell proliferation. In contrast, the level of ET(A) receptor mRNA initially decreased on day 1, and thereafter increased on days 4 and 7. Administration of FR139317 to rats with experimental glomerulonephritis induced a significant reduction in mesangial cell proliferation. In addition, in situ hybridization of preproET-1 mRNA and double-immunolabeling of ED-1 and OX-7 in a mirror image section revealed that the principal cell expressing ET-1 in glomeruli were infiltrating macrophages on day 1, and they were replaced by mesangial cells on day 4. These findings indicate that ET-1 functions as a potent mitogen for mesangial cells in vivo in an autocrine or paracrine fashion.
最近的研究表明，内皮素 -1（ET-1）在体外是系膜细胞的一种强效促有丝分裂原。为了确定ET-1在体内是否对系膜细胞发挥促有丝分裂作用，我们在系膜增生性肾小球肾炎大鼠模型中检测了ET-1及其受体的肾小球表达，并评估了特异性内皮素A（ET(A)）受体拮抗剂FR139317对该模型中系膜细胞增殖的影响。疾病诱导后第4天和第7天，肾小球中前内皮素原-1 mRNA表达水平和ET-1蛋白产生量显著增加，且这些水平的变化与肾小球细胞增殖一致。相比之下，ET(A)受体mRNA水平在第1天最初下降，随后在第4天和第7天升高。给实验性肾小球肾炎大鼠施用FR139317可显著降低系膜细胞增殖。此外，在前内皮素原-1 mRNA的原位杂交以及镜像切片中ED-1和OX-7的双重免疫标记显示，肾小球中表达ET-1的主要细胞在第1天是浸润的巨噬细胞，在第4天被系膜细胞取代。这些发现表明，ET-1在体内以自分泌或旁分泌方式作为系膜细胞的强效促有丝分裂原发挥作用。
