Takabatake Yoshitsugu, Isaka Yoshitaka, Mizui Masayuki, Kawachi Hiroshi, Takahara Shiro, Imai Enyu
Department of Nephrology, Osaka University Graduate School of Medicine (A8), Suita 565-0871, Japan.
Biochem Biophys Res Commun. 2007 Nov 16;363(2):432-7. doi: 10.1016/j.bbrc.2007.08.189. Epub 2007 Sep 11.
We previously demonstrated that transfection of synthetic short interfering RNAs (siRNAs) targeting against TGF-beta1 could be effective and therapeutic in silencing TGF-beta1 expression in glomerulus, thereby ameliorated the progression of matrix expansion in anti-Thy-1 model of glomerulonephritis. However, a major concern in applying RNAi to gene therapy is the prolonged existence of silencing potential in vivo.
We examined the duration of siRNA stability in kidney and muscle, and checked the tissue distribution of siRNase, eri-1. Thereafter, we tested the effect of chemically modified siRNA called siSTABLE on progressive glomerulosclerosis model.
A single introduction of siRNA for EGFP (siEGFP) or its expression vector into kidney resulted in the reduction of masangial EGFP expression only for up to two weeks, while transfection of siEGFP into the pretibial muscle silenced EGFP expression unexpectedly for more than 90 days. These observations could be explained by the different expression of eri-1 between kidney and muscle. In addition, transfection of ERI-1-resistant siSTABLE for TGF-beta1 significantly reduced glomerular matrix deposition in progressive glomerulosclerosis model.
Treatment with siRNA resistant to eri-1 may be effective and promising strategy for progressive renal disease.
