title: Blocking TGF-β1 protects the peritoneal membrane from dialysate-induced damage.
abstract: During peritoneal dialysis (PD), mesothelial cells undergo mesothelial-to-mesenchymal transition (MMT), a process associated with peritoneal-membrane dysfunction. Because TGF-β1 can induce MMT, we evaluated the efficacy of TGF-β1-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 intermediate-phenotype (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-β1 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-β1 drives the peritoneal deterioration induced by dialysis fluid and highlights a role of TGF-β1-mediated MMT in the pathophysiology of peritoneal-membrane dysfunction.
authors: Unidad de Biología Molecular and Servicio de Nefrología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
authors: Jesús
authors: J
authors: Loureiro
authors: Abelardo
authors: A
authors: Aguilera
authors: Rafael
authors: R
authors: Selgas
authors: Pilar
authors: P
authors: Sandoval
authors: Patricia
authors: P
authors: Albar-Vizcaíno
authors: María Luisa
authors: ML
authors: Pérez-Lozano
authors: Vicente
authors: V
authors: Ruiz-Carpio
authors: Pedro L
authors: PL
authors: Majano
authors: Santiago
authors: S
authors: Lamas
authors: Fernando
authors: F
authors: Rodríguez-Pascual
authors: Francisco
authors: F
authors: Borras-Cuesta
authors: Javier
authors: J
authors: Dotor
authors: Manuel
authors: M
authors: López-Cabrera
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D054338:Cell Transdifferentiation / Q000187:drug effects*; D002478:Cells, Cultured; D015314:Dialysis Solutions / Q000009:adverse effects; D005260:Female; D007274:Injections, Intraperitoneal; D007633:Keratins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D056627:Peritoneal Fibrosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010537:Peritoneum / Q000473:pathology*; D010641:Phenotype; D018125:Receptors, Transforming Growth Factor beta / Q000627:therapeutic use; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D015314:Dialysis Solutions; C562050:P17 peptide; D010446:Peptide Fragments; D010455:Peptides; D018125:Receptors, Transforming Growth Factor beta; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; C504795:TGF-beta1 type III receptor (730-743), human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D007633:Keratins