siRNA-based therapy ameliorates glomerulonephritis.
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.
Shimizu
Hideki
H
Department of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Hori
Yuichi
Y
Kaname
Shinya
S
Yamada
Koei
K
Nishiyama
Nobuhiro
N
Matsumoto
Satoru
S
Miyata
Kanjiro
K
Oba
Makoto
M
Yamada
Akira
A
Kataoka
Kazunori
K
Fujita
Toshiro
T
D000818:Animals; D015316:Genetic Therapy / Q000379:methods; D005921:Glomerulonephritis / Q000235:genetics / Q000628:therapy*; D007678:Kidney Glomerulus; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics*; D034741:RNA, Small Interfering
D034741:RNA, Small Interfering; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1