Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy
Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy
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DOI：
10.1038/labinvest.3700400
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发表时间：
2006-04-01
影响因子：
5
通讯作者：
Doi, T
中科院分区：
文献类型：
--
作者：
Matsubara, T;Abe, H;Doi, T
糖尿病肾病是终末期肾脏疾病的主要原因，肾小球系膜基质扩张是糖尿病肾病的标志。然而，系膜基质扩张发展的确切机制尚不清楚。参与系膜基质扩张的关键成分是IV型胶原（Col4）。最近，我们报道了Smad1在体外糖尿病条件下转录调节Col4的表达。在这里，我们发现Col4的直接调节剂在体内系膜基质扩张中也起着至关重要的作用。链脲佐菌素诱导的糖尿病大鼠是早期糖尿病肾病的模型，在24周时出现不同程度的系膜基质扩张。Western blot和免疫组化分析显示，Smad1在肾小球系膜基质扩增的糖尿病大鼠肾小球中表达显著升高。此外，肾小球Smad1的表达与肾小球Col4和平滑肌α -肌动蛋白（alpha- sma）的表达密切相关，而蛋白尿或肾小球滤过率与系膜基质扩张无关。我们还发现尿中Smad1的分泌与系膜基质扩张的严重程度密切相关。在培养的系膜细胞中，Smad1的表达上调了系膜基质扩增关键分子Col4和α - sma的转录活性。这些数据表明Smad1在糖尿病肾病早期系膜基质扩张中起关键作用。我们的数据表明尿Smad1可能是糖尿病肾病系膜基质扩张的代表性诊断标志物。
Diabetic nephropathy is the leading cause of end-stage renal disease, and glomerular mesangial matrix expansion is the hallmark in diabetic nephropathy. However, the precise mechanism for the development of mesangial matrix expansion has remained unknown. The key component involved in mesangial matrix expansion is type IV collagen (Col4). Recently, we have reported that Smad1 transcriptionally regulates expression of Col4 under diabetic conditions in vitro. Here we show that this direct regulator of Col4 also plays a crucial role for mesangial matrix expansion in vivo. Streptozotocin-induced diabetic rats are the model of incipient diabetic nephropathy, and showed various levels of mesangial matrix expansion at 24 weeks. The glomerular expression of Smad1 was significantly increased in diabetic rats with more mesangial matrix expansion by Western blot and immunohistochemical analysis. Furthermore, the glomerular expression of Smad1 was closely correlated with the glomerular expression of Col4 and smooth muscle alpha actin (alpha-SMA), while albuminuria or glomerular filtration rate was not correlated with mesangial matrix expansion. We also found that urinary excretion of Smad1 was closely associated with the severity of mesangial matrix expansion. In cultured mesangial cells expression of Smad1 upregulated the transcriptional activity of key molecules in mesangial matrix expansion, such as Col4 and alpha-SMA. These data indicate the critical involvement of Smad1 in mesangial matrix expansion in the early phase of diabetic nephropathy. Our data imply that urinary Smad1 might be a representative diagnostic marker for mesangial matrix expansion in diabetic nephropathy.