Ren S.Johnson B.G.Kida Y.Ip C.Davidson K.C.SHUEI-LIONG LINKobayashi A.Lang R.A.Hadjantonakis A.-K.Moon R.T.Duffield J.S.2021-01-122021-01-1220130027-8424https://www.scopus.com/inward/record.uri?eid=2-s2.0-84872867267&doi=10.1073%2fpnas.1211179110&partnerID=40&md5=43d4179cf95a76f0ffb0a2f0212a1520https://scholars.lib.ntu.edu.tw/handle/123456789/540340Fibrosis 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]SDG3beta 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; upregulationjournal article10.1073/pnas.1211179110233026952-s2.0-84872867267