Institute of Nephrology, Cardiff University, Heath Park Campus, Cardiff, UK.
J Am Soc Nephrol. 2010 Mar;21(3):438-47. doi: 10.1681/ASN.2009050530. Epub 2010 Jan 7.
The role of microRNAs (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 miR-192 correlated with tubulointerstitial fibrosis and low estimated GFR. In vitro, treatment of PTCs with TGF-beta1 decreased miR-192 expression. Overexpression of miR-192 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.
微小 RNA（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，我们对高糖和对照条件下培养的近端肾小管细胞（PTC）进行了表达谱分析。我们鉴定了 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，我们对来自肾活检福尔马林固定、石蜡包埋组织的混合 RNA 进行了 miR 表达谱分析。我们研究了三组已确诊的糖尿病肾病患者，并检测到 365 个 miRs 中的 103 个。两个 miR 在进展者和非进展者之间的差异超过两倍，12 个 miR 在晚期表现者和其他活检之间的差异超过两倍。我们注意到 miR-192 表达的变化最大，晚期表现者的表达明显降低。此外，在个别活检中，miR-192 的低表达与肾小管间质纤维化和低估计肾小球滤过率相关。在体外，用 TGF-β1 处理 PTCs 会降低 miR-192 的表达。miR-192 的过表达抑制了 E-Box 抑制剂 ZEB1 和 ZEB2 的表达，从而抑制了 TGF-β 介导的 E-钙黏蛋白的下调。总之，miR-192 表达的丧失与体内糖尿病肾病中纤维化增加和估计肾小球滤过率降低相关，可能通过增强 TGF-β 介导的 PTC 中 E-钙黏蛋白的下调。
