WNT signaling is required for peritoneal membrane angiogenesis.

Abstract

The wingless-type mouse mammary tumor virus integration site family (WNT) signaling pathway is involved in wound healing and fibrosis. We evaluated the WNT signaling pathway in peritoneal membrane injury. We assessed WNT1 protein expression in the peritoneal effluents of 54 stable peritoneal dialysis (PD) patients and WNT-related gene expression in ex vivo mesothelial cell cultures from 21 PD patients. In a transforming growth factor-β (TGF-β)-mediated animal model of peritoneal fibrosis, we evaluated regulation of the WNT pathway and the effect of WNT inhibition on peritoneal fibrosis and angiogenesis. WNT1 and WNT2 gene expression were positively correlated with peritoneal membrane solute transport in PD patients. In the mouse peritoneum, TGF-β-induced peritoneal fibrosis was associated with increased expression of WNT2 and WNT4. Peritoneal β-catenin protein was significantly upregulated after infection with adenovirus expressing TGF-β (AdTGF-β) along with elements of the WNT signaling pathway. Treatment with a β-catenin inhibitor (ICG-001) in mice with AdTGF-β-induced peritoneal fibrosis resulted in attenuation of peritoneal angiogenesis and reduced vascular endothelial growth factor. Similar results were also observed with the WNT antagonist Dickkopf-related protein (DKK)-1. In addition to this, DKK-1 blocked epithelial-mesenchymal transition and increased levels of the cell adhesion protein E-cadherin. We provide evidence that WNT signaling is active in the setting of experimental peritoneal fibrosis and WNT1 correlates with patient peritoneal membrane solute transport in PD patients. Intervention in this pathway is a possible therapy for peritoneal membrane injury.

• Authors: Manreet Padwal, Genyang Cheng, Limin Liu, Felix Boivin, Azim S Gangji, Kenneth S Brimble, Darren Bridgewater, Peter J Margetts
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 314 Issue 6 Pg. F1036-F1045 (06 01 2018) ISSN: 1522-1466 [Electronic] United States
• PMID: 29363326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CTNNB1 protein, mouse
• Transforming Growth Factor beta1
• WNT1 protein, human
• Wnt Proteins
• Wnt1 Protein
• Wnt4 Protein
• Wnt4 protein, mouse
• beta Catenin

Topics

• Aged
• Animals
• Cells, Cultured
• Disease Models, Animal
• Epithelial Cells (metabolism, pathology)
• Epithelial-Mesenchymal Transition
• Female
• Humans
• Male
• Mice, Inbred C57BL
• Middle Aged
• Neovascularization, Pathologic
• Peritoneal Dialysis (adverse effects)
• Peritoneal Fibrosis (etiology, genetics, metabolism, pathology)
• Peritoneum (blood supply, metabolism, pathology)
• Transforming Growth Factor beta1 (genetics, metabolism)
• Wnt Proteins (genetics, metabolism)
• Wnt Signaling Pathway
• Wnt1 Protein (genetics, metabolism)
• Wnt4 Protein (genetics, metabolism)
• beta Catenin (metabolism)