title: Ultrasound-microbubble-mediated gene transfer of inducible Smad7 blocks transforming growth factor-beta signaling and fibrosis in rat remnant kidney.
abstract: Transforming growth factor (TGF)-beta1 has been shown to play a critical role in hypertensive nephropathy. We hypothesized that blocking TGF-beta1 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-beta/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.
authors.affiliation: Department of Medicine, Municipal Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Hou
authors.forename: Wansheng
authors.initials: W
authors.lastname: Wang
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Huang
authors.forename: Ping
authors.initials: P
authors.lastname: Fu
authors.forename: Tso-Hsiao
authors.initials: TH
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Sheikh-Hamad
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004318:Doxycycline / Q000494:pharmacology; D005355:Fibrosis / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006973:Hypertension; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051906:Smad7 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D019076:Transgenes; D014465:Ultrasonics
chemical_list: D004268:DNA-Binding Proteins; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D004318:Doxycycline
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