Smad7 transgene attenuates peritoneal fibrosis in uremic rats treated with peritoneal dialysis

Abstract

Transforming growth factor β (TGF-β) plays a critical role in the pathogenesis of the peritoneal fibrosis that complicates long-term peritoneal dialysis (PD). We studied the TGF-β/Smad signaling pathway in peritoneal fibrosis induced in uremic rats treated with PD and explored the therapeutic potential of Smad7 to prevent fibrogenesis. After subtotal nephrectomy, uremic rats were treated with peritoneal dialysis using 4.25% dextrose-containing fluid. The peritoneum of uremic rats treated with PD demonstrated fibrosis, increased TGF-β expression, increased Smad2/3 activation, decreased Smad7 expression, and increased expression of fibrogenic and angiogenic factors. In addition, peritoneal function was impaired and its structure was altered, including a thickened submesothelial layer. In rats transfected with a Smad7 transgene using an ultrasound-microbubble-mediated system, peritoneal fibrosis was attenuated, peritoneal function was improved, and Smad2/3 activation was inhibited. We suggest that administration of Smad7 inhibits peritoneal fibrogenesis in uremic rats treated with PD by correcting the imbalance between downregulated Smad7 and activated Smad2/3. Blockade of the TGF-β/Smad signaling pathway may represent a novel therapeutic approach to prevent peritoneal fibrosis in patients treated with PD. Copyright © 2007 by the American Society of Nephrology.