Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells

We investigated the effectiveness of the transforming growth factor beta-1 (TGF-β) receptor inhibitor {"type":"entrez-nucleotide","attrs":{"text":"GW788388","term_id":"293585730","term_text":"GW788388"}}GW788388 on the epithelial to mesenchymal transition (EMT) using human peritoneal mesothelial cells (HPMCs) and examined the effectiveness of {"type":"entrez-nucleotide","attrs":{"text":"GW788388","term_id":"293585730","term_text":"GW788388"}}GW788388 on the peritoneal membrane using a peritoneal fibrosis mouse model. HPMCs were treated with TGF-β with or without {"type":"entrez-nucleotide","attrs":{"text":"GW788388","term_id":"293585730","term_text":"GW788388"}}GW788388. Animal experiments were conducted on male C57/BL6 mice. Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate. {"type":"entrez-nucleotide","attrs":{"text":"GW788388","term_id":"293585730","term_text":"GW788388"}}GW788388 was administered by once-daily oral gavage. The morphological change, cell migration, and invasion resulted from TGF-β treatment, but these changes were attenuated by cotreatment with {"type":"entrez-nucleotide","attrs":{"text":"GW788388","term_id":"293585730","term_text":"GW788388"}}GW788388. TGF-β-treated HPMCs decreased the level of the epithelial cell marker and increased the levels of the mesenchymal cell markers. Cotreatment with {"type":"entrez-nucleotide","attrs":{"text":"GW788388","term_id":"293585730","term_text":"GW788388"}}GW788388 reversed these changes. Phosphorylated Smad2 and Smad3 protein levels were stimulated with TGF-β and the change was attenuated by cotreatment with {"type":"entrez-nucleotide","attrs":{"text":"GW788388","term_id":"293585730","term_text":"GW788388"}}GW788388. For the peritoneal fibrosis mice, thickness and collagen deposition of parietal peritoneum was increased, but this change was attenuated by cotreatment with {"type":"entrez-nucleotide","attrs":{"text":"GW788388","term_id":"293585730","term_text":"GW788388"}}GW788388. {"type":"entrez-nucleotide","attrs":{"text":"GW788388","term_id":"293585730","term_text":"GW788388"}}GW788388, an orally available potent TGF-β receptor type 1 inhibitor, effectively attenuated TGF-β-induced EMT in HPMCs. Cotreatment with {"type":"entrez-nucleotide","attrs":{"text":"GW788388","term_id":"293585730","term_text":"GW788388"}}GW788388 improved peritoneal thickness and fibrosis, and recovered peritoneal membrane function in a peritoneal fibrosis mouse model.