LRP-6 is co-receptor for multiple fibrogenic pathways in pericytes and myofibroblasts that are inhibited by DKK-1

Division of Nephrology and Center for Lung Biology, Department of Medicine and Pathology, Howard Hughes Medical Institute, and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 01/2013; 110(4). DOI: 10.1073/pnas.1211179110
Source: PubMed

ABSTRACT Fibrosis of vital organs is a major public health problem with limited therapeutic options. Mesenchymal cells including microvascular mural cells (pericytes) are major progenitors of scar-forming myofibroblasts in kidney and other organs. Here we show pericytes in healthy kidneys have active WNT/β-catenin signaling responses that are markedly up-regulated following kidney injury. Dickkopf-related protein 1 (DKK-1), a ligand for the WNT coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP-5 and LRP-6) and an inhibitor of WNT/β-catenin signaling, effectively inhibits pericyte activation, detachment, and transition to myofibroblasts in vivo in response to kidney injury, resulting in attenuated fibrogenesis, capillary rarefaction, and inflammation. DKK-1 blocks activation and proliferation of established myofibroblasts in vitro and blocks pericyte proliferation to PDGF, pericyte migration, gene activation, and cytoskeletal reorganization to TGF-β or connective tissue growth factor. These effects are largely independent of inhibition of downstream β-catenin signaling. DKK-1 acts predominantly by inhibiting PDGF-, TGF-β-, and connective tissue growth factor-activated MAPK and JNK signaling cascades, acting via LRP-6 with associated WNT ligand. Biochemically, LRP-6 interacts closely with PDGF receptor β and TGF-β receptor 1 at the cell membrane, suggesting that it may have roles in pathways other than WNT/β-catenin. In summary, DKK-1 blocks many of the changes in pericytes required for myofibroblast transition and attenuates established myofibroblast proliferation/activation by mechanisms dependent on LRP-6 and WNT ligands but not the downstream β-catenin pathway.

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    • "Renal β-catenin is increased in experimental models of renal fibrosis (He et al., 2009; Ren et al., 2013; Surendran et al., 2005) and its systemic inhibition can reduce fibrosis (Hao et al., 2011). However, although DKK-1, a Wnt antagonist significantly reduced renal β-catenin abundance (He et al., 2009), the anti-fibrotic effects of DKK-1 were found to be independent of β-catenin in UUO and I/R models of fibrosis (Ren et al., 2013). Moreover, gene deletion of β-catenin in tubular epithelium did not reduce renal fibrosis (Zhou et al., 2013). "
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    • "Wnt/β-catenin signaling modulates the recruitment and resolution of inflammatory cells Since Wnt/β-catenin signaling is required for blastema formation and regenerative outgrowth in zebrafish caudal fins (Ito et al., 2007; Kawakami et al., 2006; Poss et al., 2000; Stoick-Cooper et al., 2007a,b), but also modulates inflammatory processes including scar formation, fibrosis, wound healing and tissue remodeling in mammals (French et al., 2004; Ren et al., 2013; Koch et al., 2011), we investigated whether there might be a role for Wnt/β-catenin signaling in regulating inflammation during fin regeneration. "
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