Smad7 gene transfer inhibits peritoneal fibrosis

Fibrosis mediated by transforming growth factor-beta (TGF-beta) is a common cause of peritoneal dialysis (PD) failure. In a model of peritoneal fibrosis, we tested the effect of Smad7, an inhibitor of TGF-beta signaling, using an ultrasound-microbubble-mediated delivery system. Rats were given daily PD for 4 weeks and received Smad7 or control plasmid transfer. The ultrasound technique enhanced Smad7 expression in a dose-dependent manner in more than 80% of the peritoneal cells after 3 days. The expression decreased by 14 days, but this was corrected by a second gene transfer. The overexpression of Smad7 substantially inhibited Smad2/3 activation, TGF-beta, plasminogen activator inhibitor-1, extracellular matrix, and myofibroblast mRNA, and protein expression in the peritoneal cells. The decreased peritoneal injury included the rise of mass transfer of glucose, a reduction of the ultrafiltration rate, and fibrotic thickening. Our studies suggest that ultrasound-mediated Smad7 gene delivery may be useful in the prevention or treatment of dialysis-induced peritoneal fibrosis.