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

Am J Pathol. 2005 Mar;166(3):761-71. doi: 10.1016/s0002-9440(10)62297-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Pressure
  • Blotting, Western
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Doxycycline / pharmacology
  • Fibrosis / metabolism
  • Gene Transfer Techniques*
  • Genetic Vectors
  • Hypertension
  • Immunohistochemistry
  • Immunoprecipitation
  • Kidney / metabolism*
  • Kidney / pathology
  • Male
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Smad7 Protein
  • Time Factors
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Transforming Growth Factor beta / metabolism*
  • Transgenes
  • Ultrasonics*


  • DNA-Binding Proteins
  • Smad7 Protein
  • Smad7 protein, rat
  • Trans-Activators
  • Transforming Growth Factor beta
  • Doxycycline