Ultrasound-microbubble-mediated gene transfer of inducible Smad7 blocks transforming growth factor-β signaling and fibrosis in rat remnant kidney

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

Research output: Contribution to journalArticle

149 Citations (Scopus)

Abstract

Transforming growth factor (TGF)-β1 has been shown to play a critical role in hypertensive nephropathy. We hypothesized that blocking TGF-β1 signaling could attenuate renal fibrosis hi 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 hi 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-β/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.

Original languageEnglish
Pages (from-to)761-771
Number of pages11
JournalAmerican Journal of Pathology
Volume166
Issue number3
Publication statusPublished - Mar 2005

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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