Loss of MicroRNA-192 Promotes Fibrogenesis in Diabetic Nephropathy
Loss of MicroRNA-192 Promotes Fibrogenesis in Diabetic Nephropathy
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DOI：
10.1681/asn.2009050530
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发表时间：
2010-03-01
影响因子：
13.6
通讯作者：
Fraser, Donald
中科院分区：
文献类型：
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作者：
Krupa, Aleksandra;Jenkins, Robert;Fraser, Donald
MicroRNS(MiRs)是调节基因表达的内源性RNA寡核苷酸，其在糖尿病肾病中的作用尚不清楚。在这里，我们进行了培养的近端小管细胞(PTCs)在高糖和对照条件下的表达谱分析。我们确定了328个microRNAs中的103个表达，但没有观察到葡萄糖诱导的表达变化。接下来，我们从福尔马林固定的、石蜡包埋的肾活检组织中提取的RNA中进行miR表达谱分析。我们研究了三组确诊为糖尿病肾病的患者，检测到了365个MIR中的103个。进展者和非进展者之间有两个MIR相差超过两倍，晚期进展者和其他活检组织之间有12个MIR不同。我们注意到mir-192的表达变化最大，在晚期演讲者中明显较低。此外，在个别活检组织中，miR0192的低表达与肾小管间质纤维化和低估计的GFR相关。在体外，经转化生长因子-β1处理的PTCs可降低miR-192的表达。IRRI的过表达抑制了E-Box抑制基因ZEB1和ZEB2的表达，从而对抗了转化生长因子-β介导的E-钙粘蛋白的下调。总之，在体内糖尿病肾病中miR-192的表达缺失与纤维化增加和估计的GFR减少相关，可能是通过增强转化生长因子-β介导的PTCs中E-钙粘蛋白的下调而实现的。
The role of microRNS (miRs), which are endogenous RNA oligonucleotides that regulate gene expression, in diabetic nephropathy is unknown. Here, we performed expression profiling of cultured proximal tubular cells (PTCs) under high-glucose and control conditions. We identified expression of 103 of 328 microRNAs but did not observe glucose-induced changes in expression.. Next, we performed miR expression profiling in pooled RNA from formalin-fixed, paraffin-embedded tissue from renal biopsies. We studied three groups of patients with established diabetic nephropathy and detected 103 of 365 miRs. Two miRs differed by more than two-fold between progressors and nonprogressors, and 12 miRs differed between late presenters and other biopsies. We noted the greatest change in mir-192 expression, which was significantly lower in late presenters. Furthermore, in individual biopsies, low expression of miR0192 correlated with tubulointerstitial fibrosis and low estimated GFR. In vitro, treatment of PTCs with TGF-beta 1 decreased miR-192 expression. Overexpression of Irri suppressed expression of the E-Box repressors ZEB1 and ZEB2, thereby opposing TGF-beta-mediated downregulation of E-cadherin. In summary, loss of miR-192 expression associates with increased fibrosis and decreased estimated GFR in diabetic nephropathy in vivo, perhaps by enhancing TGF-beta-mediated downregulation of E-cadherin in PTCs.