Inhibiting MicroRNA-192 Ameliorates Renal Fibrosis in Diabetic Nephropathy
Inhibiting MicroRNA-192 Ameliorates Renal Fibrosis in Diabetic Nephropathy
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DOI：
10.1681/asn.2011050485
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发表时间：
2012-03-01
影响因子：
13.6
通讯作者：
Natarajan, Rama
中科院分区：
文献类型：
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作者：
Putta, Sumanth;Lanting, Linda;Natarajan, Rama
TG-β1上调培养的肾小球系膜细胞和糖尿病小鼠肾小球中的microRNA-192(miR-192)。MIR-192不仅通过靶向E-box抑制物ZEB1/2增加胶原蛋白的表达，而且还调节其他肾脏miRNAs，提示它可能是糖尿病肾病的治疗靶点。我们评价了锁定核酸(LNA)修饰的miR-192抑制剂，命名为LNA-anti-miR-192，在糖尿病肾病小鼠模型中的疗效。LNA-抗miR-192显著降低了正常和链脲佐菌素诱导的糖尿病小鼠肾脏中miR-192的水平，但没有降低miR-194的水平。在糖尿病小鼠的肾脏中，抑制miR-192显著增加ZEB1/2，降低胶原、转化生长因子-β和纤维连接蛋白的基因表达；免疫染色证实了这些肾纤维化介质的下调。此外，LNA-anti-miR-192可减少这些糖尿病小鼠的蛋白尿。总之，肾脏miR-192的特异性减少减少了肾脏纤维化和改善了蛋白尿，为基于miRNA的翻译方法治疗糖尿病肾病的可能性提供了支持。
TG-beta 1 upregulates microRNA-192 (miR-192) in cultured glomerular mesangial cells and in glomeruli from diabetic mice. miR-192 not only increases collagen expression by targeting the E-box repressors Zeb1/2 but also modulates other renal miRNAs, suggesting that it may be a therapeutic target for diabetic nephropathy. We evaluated the efficacy of a locked nucleic acid (LNA)-modified inhibitor of miR-192, designated LNA-anti-miR-192, in mouse models of diabetic nephropathy. LNA-anti-miR-192 significantly reduced levels of miR-192, but not miR-194, in kidneys of both normal and streptozotocin-induced diabetic mice. In the kidneys of diabetic mice, inhibition of miR-192 significantly increased Zeb1/2 and decreased gene expression of collagen, TGF-beta, and fibronectin; immunostaining confirmed the downregulation of these mediators of renal fibrosis. Furthermore, LNA-anti-miR-192 attenuated proteinuria in these diabetic mice. In summary, the specific reduction of renal miR-192 decreases renal fibrosis and improves proteinuria, lending support for the possibility of an anti-miRNA-based translational approach to the treatment of diabetic nephropathy.