BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
J Am Soc Nephrol. 2014 Jan;25(1):65-80. doi: 10.1681/ASN.2013010072. Epub 2013 Oct 24.
Renal tubulointerstitial fibrosis is the common end point of progressive renal disease. MicroRNA (miR)-214 and miR-21 are upregulated in models of renal injury, but the function of miR-214 in this setting and the effect of its manipulation remain unknown. We assessed the effect of inhibiting miR-214 in an animal model of renal fibrosis. In mice, genetic deletion of miR-214 significantly attenuated interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Treatment of wild-type mice with an anti-miR directed against miR-214 (anti-miR-214) before UUO resulted in similar antifibrotic effects, and in vivo biodistribution studies demonstrated that anti-miR-214 accumulated at the highest levels in the kidney. Notably, in vivo inhibition of canonical TGF-β signaling did not alter the regulation of endogenous miR-214 or miR-21. Whereas miR-21 antagonism blocked Smad 2/3 activation, miR-214 antagonism did not, suggesting that miR-214 induces antifibrotic effects independent of Smad 2/3. Furthermore, TGF-β blockade combined with miR-214 deletion afforded additional renal protection. These phenotypic effects of miR-214 depletion were mediated through broad regulation of the transcriptional response to injury, as evidenced by microarray analysis. In human kidney tissue, miR-214 was detected in cells of the glomerulus and tubules as well as in infiltrating immune cells in diseased tissue. These studies demonstrate that miR-214 functions to promote fibrosis in renal injury independent of TGF-β signaling in vivo and that antagonism of miR-214 may represent a novel antifibrotic treatment in the kidney.
肾间质纤维化是进行性肾病的共同终点。miR-214 和 miR-21 在肾损伤模型中上调，但 miR-214 在这种情况下的功能及其操作的影响尚不清楚。我们评估了在肾纤维化动物模型中抑制 miR-214 的效果。在小鼠中，miR-214 的遗传缺失显著减弱了单侧输尿管梗阻 (UUO) 引起的间质纤维化。在 UUO 前用针对 miR-214 的反义 miR (anti-miR-214) 处理野生型小鼠，导致类似的抗纤维化作用，体内生物分布研究表明，anti-miR-214 在肾脏中积累水平最高。值得注意的是，体内抑制经典 TGF-β 信号传导不会改变内源性 miR-214 或 miR-21 的调节。虽然 miR-21 拮抗作用阻断了 Smad 2/3 激活，但 miR-214 拮抗作用没有，表明 miR-214 诱导抗纤维化作用独立于 Smad 2/3。此外，TGF-β 阻断与 miR-214 缺失相结合提供了额外的肾脏保护。miR-214 耗竭的这些表型作用是通过对损伤的转录反应进行广泛调节介导的，这一点通过微阵列分析得到了证明。在人类肾脏组织中，miR-214 在肾小球和肾小管的细胞以及病变组织中的浸润免疫细胞中被检测到。这些研究表明，miR-214 在体内独立于 TGF-β 信号传导促进肾损伤中的纤维化，并且拮抗 miR-214 可能代表肾脏中的一种新型抗纤维化治疗方法。
