title: Gremlin promotes peritoneal membrane injury in an experimental mouse model and is associated with increased solute transport in peritoneal dialysis patients.
abstract: The peritoneal membrane becomes damaged in patients on peritoneal dialysis (PD). Gremlin 1 (GREM1) inhibits bone morphogenic proteins (BMPs) and plays a role in kidney development and fibrosis. We evaluated the role of gremlin in peritoneal fibrosis and angiogenesis. In a cohort of 32 stable PD patients, GREM1 concentration in the peritoneal effluent correlated with measures of peritoneal membrane damage. AdGrem1, an adenovirus to overexpress gremlin in the mouse peritoneum, induced submesothelial thickening, fibrosis, and angiogenesis in C57BL/6 mice, which was associated with decreased expression of BMP4 and BMP7. There was evidence of mesothelial cell transition to a mesenchymal phenotype with increased α smooth muscle actin expression and suppression of E-cadherin. Some of the GREM1 effects may be reversed with recombinant BMP7 or a pan-specific transforming growth factor β (TGF-β) antibody. Neovascularization was not inhibited with a TGF-β antibody, suggesting a TGF-β-independent angiogenic mechanism. Swiss/Jackson Laboratory (SJL) mice, which are resistant to TGF-β-induced peritoneal fibrosis, responded in a similar fashion to AdGrem1 as did C57BL/6 mice with fibrosis, angiogenesis, and mesothelial-to-mesenchymal transition. GREM1 was associated with up-regulated TGF-β expression in both SJL and C57BL/6 mice, but SJL mice demonstrated a defective TGF-β-induced GREM1 expression. In summary, GREM1 induces fibrosis and angiogenesis in mouse peritoneum and is associated with increased solute transport in these PD patients.
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Imad
authors.initials: I
authors.lastname: Siddique
authors.affiliation: Division of Nephrology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Curran
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Ghayur
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Limin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Children's Hospital Los Angeles, University of Southern California, Los Angeles, California.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Renal Division, Baxter Healthcare, McGaw Park, Illinois.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hoff
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Azim S
authors.initials: AS
authors.lastname: Gangji
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: K Scott
authors.initials: KS
authors.lastname: Brimble
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: margetts@mcmaster.ca.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Margetts
mesh_terms: D000368:Aged; D000818:Animals; D001692:Biological Transport; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D056627:Peritoneal Fibrosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D010537:Peritoneum / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053773:Transforming Growth Factor beta1