Gonda Diabetes Center, Beckman Research Institute of the City of Hope, Duarte, California, USA.
Kidney Int. 2011 Aug;80(4):358-68. doi: 10.1038/ki.2011.43. Epub 2011 Mar 9.
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. As 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.
肾细胞中增强的转化生长因子-β1（TGF-β1）表达促进糖尿病肾病进展过程中的纤维化和肥大。TGF-β1 启动子受 E 盒调节因子、上游刺激因子（USF）的正向调控，以响应糖尿病（高血糖）条件；然而，TGF-β1 是否自身受到调节尚不清楚。由于 microRNAs（miRNAs）的变化与肾脏疾病有关，我们测试了它们在这个过程中的参与情况。在小鼠系膜细胞中，miR-192（miR-192）或 miR-200b/c 上调 TGF-β1 水平。1 型（链脲佐菌素）和 2 型（db/db）糖尿病小鼠肾小球中 miR-200b/c 的含量增加，以及体外用 TGF-β1 处理的小鼠系膜细胞中 miR-200b/c 的含量也增加。miR-192 在系膜细胞中也上调了 miR-200b/c 的水平，表明 miR-200b/c 是 miR-192 的下游产物。TGF-β1 启动子的活性被 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 TGF-β1 启动子 E 盒结合位点上的激活剂 USF1 和 Tfe3 的占有率，减少了抑制因子 Zeb1 的占有率。miR-192 的抑制剂降低了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 调节的回路可能放大 TGF-β1 信号，加速糖尿病肾病等慢性纤维化疾病的发展。
