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siRNA-Based Therapy Ameliorates Glomerulonephritis

热2 qxm123 添加于 2010-4-4 20:09 | 2328 次阅读 | 0 个评论

作者
Shimizu H, Hori Y, Kaname S, Yamada K, Nishiyama N, Matsumoto S, Miyata K, Oba M, Yamada A, Kataoka K, Fujita T
摘要
RNA interference by short interfering RNAs (siRNAs) holds promise as a therapeutic strategy, but use of siRNAs in vivo remains limited. Here, we developed a system to target delivery of siRNAs to glomeruli via poly(ethylene glycol)-poly(l-lysine)-based vehicles. The siRNA/nanocarrier complex was approximately 10 to 20 nm in diameter, a size that would allow it to move across the fenestrated endothelium to access to the mesangium. After intraperitoneal injection of fluorescence-labeled siRNA/nanocarrier complexes, we detected siRNAs in the blood circulation for a prolonged time. Repeated intraperitoneal administration of a mitogen-activated protein kinase 1 (MAPK1) siRNA/nanocarrier complex suppressed glomerular MAPK1 mRNA and protein expression in a mouse model of glomerulonephritis; this improved kidney function, reduced proteinuria, and ameliorated glomerular sclerosis. Furthermore, this therapy reduced the expression of the profibrotic markers TGF-beta1, plasminogen activator inhibitor-1, and fibronectin. In conclusion, we successfully silenced intraglomerular genes with siRNA using nanocarriers. This technique could aid the investigation of molecular mechanisms of renal disease and has potential as a molecular therapy of glomerular diseases.
详细资料
- 文献种类:期刊
- 期刊名称: Journal of the American Society of Nephrology
- 期刊缩写: Journal of the American Society of Nephrology
- 期卷页: 2010年第21卷第4期 622-633页
- ISBN: 1046-6673
相关链接 DOI URL
附件
siRNA-Based Therapy Ameliorates Glomerulonephritis

qxm123 的文献笔记订阅

核糖核酸短干扰RNA（siRNAs）的干扰持有作为治疗策略，但在体内使用的siRNAs仍然有限。在这里，我们开发了一个系统目标通过聚（乙烯乙二醇的siRNA传递到肾小球），聚（L -赖氨酸）的载体的siRNA / nanocarrier复合体直径约为10至20纳米大小，允许它在内皮细胞微孔进入系膜。通过荧光标记的小干扰RNA / nanocarrier腹腔注射，我们发现siRNA在血液循环时间延长。反复腹腔注射的有丝分裂原激活蛋白激酶1（MAPK1）小干扰RNA / nanocarrier复合体抑制了小鼠模型肾小球肾炎MAPK1基因和蛋白的表达，改善肾功能、减少蛋白尿、肾小球硬化和改善。此外，这种疗法减少了纤维化标志物转化生长因子-β1，纤溶酶原激活物抑制剂1和纤维连接蛋白表达。最后，我们在肾小球内使用siRNAnanocarriers成功地沉默基因。这种技术可帮助肾脏疾病的分子机制研究，并已作为一种分子治疗肾小球疾病的潜力。

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