Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Am J Physiol Renal Physiol. 2011 Oct;301(4):F793-801. doi: 10.1152/ajprenal.00273.2011. Epub 2011 Jul 20.
Renal fibrosis is a final stage of many forms of kidney disease and leads to impairment of kidney function. The molecular pathogenesis of renal fibrosis is currently not well-understood. microRNAs (miRNAs) are important players in initiation and progression of many pathologic processes including diabetes, cancer, and cardiovascular disease. However, the role of miRNAs in kidney injury and repair is not well-characterized. In the present study, we found a unique miRNA signature associated with unilateral ureteral obstruction (UUO)-induced renal fibrosis. We found altered expression in UUO kidneys of miRNAs that have been shown to be responsive to stimulation by transforming growth factor (TGF)-β1 or TNF-α. Among these miRNAs, miR-21 demonstrated the greatest increase in UUO kidneys. The enhanced expression of miR-21 was located mainly in distal tubular epithelial cells. miR-21 expression was upregulated in response to treatment with TGF-β1 or TNF-α in human renal tubular epithelial cells in vitro. Furthermore, we found that blocking miR-21 in vivo attenuated UUO-induced renal fibrosis, presumably through diminishing the expression of profibrotic proteins and reducing infiltration of inflammatory macrophages in UUO kidneys. Our data suggest that targeting specific miRNAs could be a novel therapeutic approach to treat renal fibrosis.
肾脏纤维化是许多形式的肾脏疾病的终末期阶段，导致肾功能受损。肾脏纤维化的分子发病机制目前还不完全清楚。microRNAs（miRNAs）是许多病理过程（包括糖尿病、癌症和心血管疾病）起始和进展的重要参与者。然而，miRNAs 在肾脏损伤和修复中的作用尚未得到很好的描述。在本研究中，我们发现了一个与单侧输尿管梗阻（UUO）诱导的肾脏纤维化相关的独特 miRNA 特征。我们发现，在 UUO 肾脏中，已经显示对转化生长因子（TGF）-β1 或肿瘤坏死因子（TNF）-α刺激有反应的 miRNAs 的表达发生了改变。在这些 miRNAs 中，miR-21 在 UUO 肾脏中的增加最为显著。miR-21 的增强表达主要位于远端肾小管上皮细胞中。miR-21 的表达在体外受到 TGF-β1 或 TNF-α处理的人肾小管上皮细胞中上调。此外，我们发现体内阻断 miR-21 可减轻 UUO 诱导的肾脏纤维化，可能是通过减少致纤维化蛋白的表达和减少 UUO 肾脏中炎症巨噬细胞的浸润。我们的数据表明，针对特定的 miRNAs 可能是治疗肾脏纤维化的一种新的治疗方法。
