A microRNA circuit mediates transforming growth factor-β1 autoregulation in renal glomerular mesangial cells.
A microRNA circuit mediates transforming growth factor-β1 autoregulation in renal glomerular mesangial cells.
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DOI：
10.1038/ki.2011.43
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发表时间：
2011-08
影响因子：
19.6
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中科院分区：
文献类型：
--
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在糖尿病肾病的发展过程中，肾细胞中转化生长因子-β1 （TGF-β1）表达增强促进了纤维化和肥厚。TGF-β1启动子受到E-box调节因子上游刺激因子（USFs）的正向控制，以应对糖尿病（高血糖）状况；然而，TGF-β1是否由自身自动调节尚不清楚。由于微小rna （miRNAs）的变化与肾脏疾病有关，我们测试了它们在这一过程中的参与程度。小鼠系膜细胞中TGF-β1水平被microRNA-192 （miR-192）或miR-200b/c上调。1型（链脲佐菌素）和2型（db/db）糖尿病小鼠肾小球以及TGF-β1处理的小鼠系膜细胞中miR-200b/c的含量升高。miR-192也上调了系膜细胞中miR-200b/c的水平，表明miR-200b/c位于miR-192的下游。TGF-β1启动子活性被TGF-β1或miR-192上调，表明miR-192- mir -200级联诱导TGF-β1表达。TGF-β1增加了激活因子USF1和Tfe3的占用，降低了抑制因子Zeb1在TGF-β1启动子E-box结合位点的占用。miR-192抑制剂可降低小鼠系膜细胞和小鼠肾皮质中miR-200b/c、Col1a2、Col4a1和TGF-β1的表达。因此，mirna调控的回路可能会放大TGF-β1信号，加速慢性纤维化疾病，如糖尿病肾病。
Enhanced transforming growth factor-β1 (TGF-β1) expression in renal cells promotes fibrosis and hypertrophy during the progression of diabetic nephropathy. The TGF-β1 promoter is positively controlled by the E-box regulators, Upstream Stimulatory Factors (USFs), in response to diabetic (high glucose) conditions; however, it is not clear whether TGF-β1 is autoregulated by itself. Since changes in microRNAs (miRNAs) have been implicated in kidney disease, we tested their involvement in this process. TGF-β1 levels were found to be upregulated by microRNA-192 (miR-192) or miR-200b/c in mouse mesangial cells. Amounts of miR-200b/c were increased in glomeruli from type 1 (streptozotocin) and type 2 (db/db) diabetic mice, and in mouse mesangial cells treated with TGF-β1 in vitro. Levels of miR-200b/c were also upregulated by miR-192 in the mesangial cells, suggesting that miR-200b/c are downstream of miR-192. Activity of the TGF-β1 promoter was upregulated by TGF-β1 or miR-192, demonstrating that the miR-192-miR-200 cascade induces TGF-β1 expression. TGF-β1 increased the occupancy of activators USF1 and Tfe3, and decreased that of the repressor Zeb1 on the TGF-β1 promoter E-box binding sites. Inhibitors of miR-192 decreased the expression of miR-200b/c, Col1a2, Col4a1 and TGF-β1 in mouse mesangial cells, and in mouse kidney cortex. Thus, miRNA-regulated circuits may amplify TGF-β1 signaling accelerating chronic fibrotic diseases such as diabetic nephropathy.
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影响因子：
5.3
作者：
GEISER, AG;KIM, SJ;SPORN, MB
通讯作者：
SPORN, MB
影响因子：
4.5
作者：
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影响因子：
11.2
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通讯作者：
Brock, Graham J.
影响因子：
11.2
作者：
Bracken, Cameron P.;Gregory, Philip A.;Goodall, Gregory J.
通讯作者：
Goodall, Gregory J.
影响因子：
13.6
作者：
Chung, Arthur C. K.;Huang, Xiao R.;Lan, Hui Y.
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Lan, Hui Y.