Growth arrest-specific gene 6 is involved in glomerular hypertrophy in the early stage of diabetic nephropathy
Growth arrest-specific gene 6 is involved in glomerular hypertrophy in the early stage of diabetic nephropathy
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DOI：
10.1074/jbc.m213266200
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发表时间：
2003-05-16
影响因子：
4.8
通讯作者：
Doi, T
中科院分区：
文献类型：
--
作者：
Nagai, K;Arai, H;Doi, T
肾病是糖尿病最常见的并发症之一。肾小球肥大是肾病早期的标志。然而，肾小球肥大的机制仍不完全清楚。我们已经报道了Gas 6（生长抑制特异性基因6）及其受体Axl在肾小球肾炎的发展中起关键作用。在这里，我们展示了Gas 6/Axl在糖尿病肾小球肥大发病机制中的重要作用。在链脲佐菌素（STZ）诱导的糖尿病大鼠，系膜和肾小球肥大，肾小球滤过率（GFR）和蛋白尿的增加后，观察到STZ注射12周。肾小球Gas 6和Axl表达增加。华法林可抑制STZ大鼠肾小球系膜和肾小球肥大以及GFR和蛋白尿的增加。此外，我们发现STZ治疗的Gas 6基因敲除小鼠的系膜肥大比对照小鼠少。在体外实验中，我们发现用Gas 6刺激系膜细胞导致系膜细胞肥大。因此，我们发现了一个新的机制，肾小球肥大通过Gas 6/Axl介导的途径在糖尿病肾病的发展。在糖尿病患者中抑制Gas 6/Axl通路可能有利于减缓糖尿病肾病的进展。
Nephropathy is one of the most common complications of diabetes mellitus. Glomerular hypertrophy is a hallmark in the early phase of the nephropathy. The mechanism of glomerular hypertrophy, however, remains incompletely understood. We have reported that Gas6 (growth arrest-specific gene 6) and its receptor, Axl, play a key role in the development of glomerulonephritis. Here we show the important role of Gas6/Axl in the pathogenesis of diabetic glomerular hypertrophy. In streptozotocin (STZ)-induced diabetic rats, mesangial and glomerular hypertrophy and an increase in the glomerular filtration rate (GFR) and albuminuria were observed after 12 weeks of STZ injection. The glomerular expression of Gas6 and Axl was increased in those rats. Administration of warfarin inhibited mesangial and glomerular hypertrophy and the increase in GFR and albuminuria in STZ rats. Moreover, we found less mesangial hypertrophy in STZ-treated Gas6 knockout mice than control mice. In vitro we found that stimulation of mesangial cells with Gas6 resulted in mesangial cell hypertrophy. Thus we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy. Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy.