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

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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

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Microbubbles
Transforming Growth Factors
Fibrosis
Kidney
Genes
Arteriosclerosis
Doxycycline
Creatinine
Hypertension
Myofibroblasts
Kidney Diseases
Nephrectomy
Transgenes
Proteinuria
Drinking Water
Genetic Therapy
Collagen

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Ultrasound-microbubble-mediated gene transfer of inducible Smad7 blocks transforming growth factor-β signaling and fibrosis in rat remnant kidney. / Hou, Chun-Cheng; Wang, Wansheng; Huang, Xiao R.; Fu, Ping; Chen, Tso Hsiao; Sheikh-Hamad, David; Lan, Hui Y.

In: American Journal of Pathology, Vol. 166, No. 3, 03.2005, p. 761-771.

Research output: Contribution to journalArticle

Hou, Chun-Cheng ; Wang, Wansheng ; Huang, Xiao R. ; Fu, Ping ; Chen, Tso Hsiao ; Sheikh-Hamad, David ; Lan, Hui Y. / Ultrasound-microbubble-mediated gene transfer of inducible Smad7 blocks transforming growth factor-β signaling and fibrosis in rat remnant kidney. In: American Journal of Pathology. 2005 ; Vol. 166, No. 3. pp. 761-771.
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