title: LRP-6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1.
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.
authors.affiliation: Division of Nephrology and Center for Lung Biology, Department of Medicine and Pathology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Ren
authors.forename: Bryce G
authors.initials: BG
authors.lastname: Johnson
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Kida
authors.forename: Colin
authors.initials: C
authors.lastname: Ip
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Davidson
authors.forename: Shuei-Liong
authors.initials: SL
authors.lastname: Lin
authors.forename: Akio
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lang
authors.forename: Anna-Katerina
authors.initials: AK
authors.lastname: Hadjantonakis
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
mesh_terms: D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000494:pharmacology; D005355:Fibrosis; D059585:G1 Phase Cell Cycle Checkpoints; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology*; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: C526318:CCN2 protein, mouse; C495267:CTNNB1 protein, mouse; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D055513:Connective Tissue Growth Factor; D000077214:Becaplermin