Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation
Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation
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DOI：
10.1074/jbc.m310427200
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发表时间：
2004-04-02
影响因子：
4.8
通讯作者：
Doi, T
中科院分区：
文献类型：
--
作者：
Abe, H;Matsubara, T;Doi, T
长期暴露于高血糖现在被认为是糖尿病并发症的最重要的致病因素。组织或循环中高血糖导致的晚期糖基化终末产物（AGE）过多可能会严重影响糖尿病肾病的进展。在糖尿病肾病中，肾小球硬化是典型的病理特征，其特征是细胞外基质（ECM）增加。我们之前报道过α1 IV型胶原蛋白（Col4）是ECM的主要成分之一，其受AGEs上调，并且Col4的过度表达受到与启动子结合的未知转录因子的转录调节。在这里，我们通过酵母单杂交筛选将该蛋白鉴定为Smad1。使用染色质免疫沉淀和报告基因检测，我们观察到 Smad1 通过与 Col4 启动子的结合直接调节 Col4 的转录。在 AGE 处理的系膜细胞中，Smad1 与 Col4 一起被显着诱导。此外，反义吗啉对 Smad1 的抑制导致 AGE 诱导的 Col4 过量产生减少。为了阐明转化生长因子-β 和 Smad1 之间的相互作用，我们研究了激活素受体样激酶 1 (ALK1) 是否参与了这种调节。 AGE 刺激显着增加系膜细胞中 ALK1 mRNA 的表达。我们还证明 Smad1 和 ALK1 在人类糖尿病肾病中高表达。这些结果表明，Smad1表达的调节与糖尿病肾病的发生和进展有关，阻断Smad1信号传导可能有益于预防糖尿病肾病和其他各种糖尿病并发症。
Prolonged exposure to hyperglycemia is now recognized as the most significant causal factor of diabetic complications. Excessive advanced glycation end products (AGEs) as a result of hyperglycemia in tissues or in the circulation may critically affect the progression of diabetic nephropathy. In diabetic nephropathy, glomerulosclerosis is a typical pathologic feature characterized by the increase of the extracellular matrix (ECM). We have reported previously that alpha1 type IV collagen (Col4) is one of the major components of ECM, which is up-regulated by AGEs, and that the overexpression of Col4 is transcriptionally regulated by an unknown transcription factor binding to the promoter. Here we identified this protein as Smad1 by yeast one-hybrid screening. Using chromatin immunoprecipitation and reporter assay, we observed that Smad1 directly regulated transcription for Col4 through the binding of Smad1 to the promoter of Col4. Smad1 was significantly induced along with Col4 in AGE-treated mesangial cells. Moreover, suppression of Smad1 by antisense morpholino resulted in a decrease of AGE-induced Col4 overproduction. To elucidate the interaction between transforming growth factor-beta and Smad1, we investigated whether activin receptor-liked kinase1 (ALK1) was involved in this regulation. AGE stimulation significantly increased the expression of the ALK1 mRNA in mesangial cells. We also demonstrated that Smad1 and ALK1 were highly expressed in human diabetic nephropathy. These results suggest that the modulation of Smad1 expression is responsible for the initiation and progression of diabetic nephropathy and that blocking Smad1 signaling may be beneficial in preventing diabetic nephropathy and other various diabetic complications.