siRNA-based therapy ameliorates glomerulonephritis.
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| Abstract |
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.
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| Authors | Hideki Shimizu, Yuichi Hori, Shinya Kaname, Koei Yamada, Nobuhiro Nishiyama, Satoru Matsumoto, Kanjiro Miyata, Makoto Oba, Akira Yamada, Kazunori Kataoka, Toshiro Fujita |
| Journal | Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 21 Issue 4 Pg. 622-33 (Apr 2010) ISSN: 1533-3450 [Electronic] United States |
| PMID | 20203158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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