Blocking TGF-β1 protects the peritoneal membrane from dialysate-induced damage

During peritoneal dialysis (PD), mesothelial cells undergo mesothelial-to-mesenchymal transition (MMT), a process associated with peritoneal-membrane dysfunction. Because TGF- 1 can induce MMT, we evaluated the efficacy of TGF- 1-blocking peptides in modulating MMT and ameliorating peritoneal damage in a mouse model of PD. Exposure of the peritoneum to PD fluid induced fibrosis, angiogenesis, functional impairment, and the accumulation of fibroblasts. In addition to expressing fibroblast-specific protein-1 (FSP-1), some fibroblasts co-expressed cytokeratin, indicating their mesothelial origin. These intermediatephenotype (Cyto /FSP-1 ) fibroblasts had features of myofibroblasts with fibrogenic capacity. PD fluid treatment triggered the appearance of CD31 /FSP-1 and CD45 /FSP-1 cells, suggesting that fibroblasts also originate from endothelial cells and from cells recruited from bone marrow. Administration of blocking peptides significantly ameliorated fibrosis and angiogenesis, improved peritoneal function, and reduced the number of FSP-1 cells, especially in the Cyto /FSP-1 subpopulation. Conversely, overexpression of TGF- 1 in the peritoneum by adenovirus-mediated gene transfer led to a marked accumulation of fibroblasts, most of which derived from the mesothelium. Taken together, these results demonstrate that TGF- 1 drives the peritoneal deterioration induced by dialysis fluid and highlights a role of TGF- 1-mediated MMT in the pathophysiology of peritoneal-membrane dysfunctionThis work was supported by grants SAF2010-21249 and SAF2007- 61201 from the Ministerio de Ciencia e Innovacio´n to M.L.-C., by grants from Fondo de Investigaciones Sanitarias to R.S. (PI 09/0641) and A.A. (PI 07/00126), and from REDinREN (RETICS 06/0016, Fondos FEDER, EU) to R.S. This work was also partially supported by Digna Biotech, Fresenius Medical Care, and Baxter Healthcare Corporation (The Baxter Extramural Grant Program 2007)