LRP-6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1

Shuyu Ren, Bryce G. Johnson, Yujiro Kida, Colin Ip, Kathryn C. Davidson, Shuei Liong Lin, Akio Kobayashi, Richard A. Lang, Anna Katerina Hadjantonakis, Randall T. Moon, Jeremy S Duffield

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125 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1440-1445
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number4
DOIs
Publication statusPublished - 22 Jan 2013
Externally publishedYes

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