LRP-6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
110
Journal Issue
4
Pages
1440-1445
Date Issued
2013
Author(s)
Ren S.
Johnson B.G.
Kida Y.
Ip C.
Davidson K.C.
Kobayashi A.
Lang R.A.
Hadjantonakis A.-K.
Moon R.T.
Duffield J.S.
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. Dickkopfrelated protein 1 (DKK-1), a ligand for the WNT coreceptors lowdensity 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.
SDGs
Other Subjects
beta catenin; connective tissue growth factor; dickkopf 1 protein; low density lipoprotein receptor related protein 6; mitogen activated protein kinase; platelet derived growth factor receptor; receptor; transforming growth factor beta; animal cell; animal experiment; animal model; article; cell activation; cell proliferation; controlled study; fibrosis; inflammation; kidney injury; mouse; myofibroblast; nonhuman; pericyte; priority journal; signal transduction; upregulation
Publisher
National Academy of Sciences
Type
journal article