期刊
KIDNEY INTERNATIONAL
卷 79, 期 1, 页码 46-56出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2010.330
关键词
chronic kidney disease; gene therapy; renal fibrosis; TGF-beta; transcription regulation
资金
- Japanese Ministry of Education, Science, Sports, and Culture
- Nihon University
- Japan Society for the Promotion of Science for Young Scientists [20 6618]
- Project for Private Universities
Pyrrole-imidazole (PI) polyamides are small synthetic molecules that recognize and attach to the minor groove of DNA, thereby inhibiting gene transcription by blocking transcription factor binding. These derivatives can act as gene silencers inhibiting target gene expression under stimulatory conditions such as disease. To evaluate PI polyamides as treatments for the progression of renal diseases, we examined morphological effects, pharmacological properties, and the specificity of PI polyamides targeted to the transforming growth factor (TGF)-beta 1 promoter during salt-induced hypertensive nephrosclerosis in Dahl salt-sensitive rats. The targeted PI polyamide markedly reduced glomerulosclerosis and interstitial fibrosis without side effects. PI polyamide significantly decreased expression of TGF-beta 1 and extracellular matrix in the renal cortex. Microarray analysis found that only 3% of the transcripts were affected by PI polyamide, but this included decreased expression of extracellular matrix, TGF-beta 1-related cytokines, angiogenic, and cell stabilizing factors, proteinases, and renal injury-related factors. Thus, targeted PI polyamides are potential gene silencers for diseases not treatable by current remedies. Kidney International (2011) 79, 46-56; doi: 10.1038/ki.2010.330; published online 22 September 2010
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