Gas6 regulates mesangial cell proliferation through Axl in experimental glomerulonephritis
Gas6 regulates mesangial cell proliferation through Axl in experimental glomerulonephritis
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DOI：
10.1016/s0002-9440(10)64093-x
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发表时间：
2001-04-01
影响因子：
6
通讯作者：
Kita, T
中科院分区：
文献类型：
--
作者：
Yanagita, M;Arai, H;Kita, T
系膜细胞增生是肾小球疾病的标志，了解其调控机制在临床上具有重要意义。之前，我们在体外证明了生长抑制特异性基因6 （Gas6）的产物通过结合其细胞表面受体Axl来刺激系膜细胞的增殖，我们还发现华法林和Axl结合人IgG1 Fc部分的细胞外结构域（Axl-Fc）通过干扰体外Gas6/Axl通路来抑制系膜细胞的增殖。因此，在本研究中，我们研究了Gasb和Axl在注射抗Thy1抗体（Thy1 GN）诱导的系膜增生性肾小球肾炎实验模型中的体内作用。在Thy1 GN中，肾小球中Gas6和Axl的表达明显增加，且与肾小球系膜细胞增殖的进展平行。给药华法林或每日注射Axl-Fc可抑制肾小球系膜细胞的增殖，并可消除对Thy1 GN中血小板源性生长因子- b mRNA和蛋白的诱导，且华法林的抗增殖作用低于临床常规用药浓度。这些发现表明Gas6/Axl通路在体内系膜细胞增殖中起关键作用，可能是治疗肾脏疾病的潜在重要治疗靶点。
Proliferation of mesangial cells Is a hallmark of glomerular disease, and understanding its regulatory mechanism is clinically important. Previously, we demonstrated that the product of growth arrest-specific gene 6 (Gas6) stimulates mesangial cell proliferation through binding to its cell-surface receptor Axl in vitro, We also showed that warfarin and the extracellular domain of Axl conjugated with Fc portion of human IgG1 (Axl-Fc) inhibit mesangial cell proliferation by interfering the Gas6/Axl pathway in vitro. In the present study, therefore, we examined in vivo roles of Gasb and Axl in an experimental model of mesangial proliferative glomerulonephritis induced by the injection of anti-Thy1.1 antibody (Thy1 GN). In Thy1 GN, expression of Gas6 and Axl was markedly increased in glomeruli, and paralleled the progression of mesangial cell proliferation. Administration of warfarin or daily injection of Axl-Fc inhibited mesangial cell proliferation, and abolished the induction of platelet-derived growth factor-B mRNA and protein in Thy1 GN, Moreover, the anti-proliferative effect of warfarin was achieved at lower concentrations than those in routine clinical use. These findings indicate that the Gas6/Axl pathway plays a key role in mesangial cell proliferation in vivo, and could be a potentially important therapeutic target for the treatment of renal disease.