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(American Journal of Pathology. 2005;166:761-771.)
© 2005 American Society for Investigative Pathology

Ultrasound-Microbubble-Mediated Gene Transfer of Inducible Smad7 Blocks Transforming Growth Factor-ß Signaling and Fibrosis in Rat Remnant Kidney

Chun-Cheng Hou*{dagger}, Wansheng Wang{dagger}, Xiao R. Huang{dagger}, Ping Fu{dagger}, Tso-Hsiao Chen*, David Sheikh-Hamad{dagger} and Hui Y. Lan{dagger}

From the Department of Medicine,* Municipal Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan, Republic of China; and the Department of Medicine-Nephrology,{dagger} Baylor College of Medicine, Houston, Texas

Transforming growth factor (TGF)-ß1 has been shown to play a critical role in hypertensive nephropathy. We hypothesized that blocking TGF-ß1 signaling could attenuate renal fibrosis in a rat model of remnant kidney disease. Groups of six rats were subjected to 5/6 nephrectomy and received renal arterial injection of a doxycycline-regulated Smad7 gene or control empty vector using an ultrasound-microbubble-mediated system. Smad7 transgene expression within the kidney was tightly controlled by the addition of doxycycline in the daily drinking water. All animals were euthanized at week 4 for renal functional and histological examination. Hypertension of equivalent magnitude (190 to 200 mmHg) developed in both Smad7- and empty vector-treated rats. However, treatment with Smad7 substantially inhibited Smad2/3 activation and prevented progressive renal injury by inhibiting the rise of 24-hour proteinuria (P < 0.001) and serum creatinine (P < 0.001), preserving creatinine clearance (P < 0.05), and attenuating renal fibrosis and vascular sclerosis such as collagen I and III expression (P < 0.01) and myofibroblast accumulation (P < 0.001). In conclusion, TGF-ß/Smad signaling plays a critical role in renal fibrosis in a rat remnant kidney model. The ability of Smad7 to block Smad2/3 activation and attenuate renal and vascular sclerosis demonstrates that ultrasound-mediated Smad7 gene therapy may be a useful therapeutic strategy for the prevention of renal fibrosis in association with hypertension.




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