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*Department of Medicine, Baylor College of Medicine, Houston, Texas; Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan; Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia.
Correspondence to Dr. Hui Y Lan, Department of Medicine-Nephrology, Baylor College of Medicine, One Baylor Plaza, Alkek N520, Houston, TX 77030. Phone: 713-798-1303; Fax: 713-798-5010;
ABSTRACT. TGF-
is a key mediator in renal fibrosis. Kidney-targeted gene therapy with anti–TGF- strategies is expected to have therapeutic potential, but this has been hampered by concerns over the safety and practicability of viral vectors and the inefficiency of nonviral transfection techniques. The present study explored the potential role of TGF-/Smad signaling in renal fibrosis in vivo and developed a safe and effective gene therapy to specifically block TGF- signaling and renal fibrosis in a rat unilateral ureteral obstruction (UUO) model by transferring a doxycycline-regulated Smad7 gene or control empty vectors using an ultrasound-microbubble (Optison)-mediated system. The Smad7 transgene expression was tightly controlled by addition of doxycycline in the daily drinking water. Groups of six rats were sacrificed at day 7, and the transfection rate, Smad7 transgene expression, and tubulointerstitial fibrosis including 
-smooth muscle actin and collagen matrix mRNA and protein expression were determined. Compared with the non-ultrasound treatment, the combination of ultrasound with Optison largely increased the transfection rate of FITC-ODN and Smad7 transgene expression up to a 1000-fold, and this was found in all kidney tissues. Compared with normal rats, Smad7 expression within the UUO kidney was significantly reduced, and this was associated with up to a sixfold increase in Smad2 and Smad3 activation and severe tubulointerstitial fibrosis. In contrast, treatment with inducible Smad7 resulted in a fivefold increase in Smad7 expression with complete inhibition of Smad2 and Smad3 activation and tubulointerstitial fibrosis in terms of tubulointerstitial myofibroblast accumulation (85%
) and collagen I and III mRNA and protein expression (60 to 70%). In conclusion, the ultrasound-mediated inducible Smad7 gene transfer is a safe, effective, and controllable gene therapy. TGF-–mediated renal fibrosis is regulated positively by Smad2/3, but negatively by Smad7. Target blockade of TGF-/Smad signaling by expression of Smad7 may provide a new therapeutic potential for renal fibrosis. E-mail: hlan@bcm.tmc.edu
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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673
