{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T18:49:06Z","timestamp":1793386146881,"version":"4.5.0"},"reference-count":22,"publisher":"National Academy of Sciences","issue":"4","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,1,22]]},"abstract":"<jats:p>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\/\u03b2-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\/\u03b2-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-\u03b2 or connective tissue growth factor. These effects are largely independent of inhibition of downstream \u03b2-catenin signaling. DKK-1 acts predominantly by inhibiting PDGF-, TGF-\u03b2\u2013, 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 \u03b2 and TGF-\u03b2 receptor 1 at the cell membrane, suggesting that it may have roles in pathways other than WNT\/\u03b2-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 \u03b2-catenin pathway.<\/jats:p>","DOI":"10.1073\/pnas.1211179110","type":"journal-article","created":{"date-parts":[[2013,1,10]],"date-time":"2013-01-10T09:33:29Z","timestamp":1357810409000},"page":"1440-1445","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":174,"title":["LRP-6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1"],"prefix":"10.1073","volume":"110","author":[{"given":"Shuyu","family":"Ren","sequence":"first","affiliation":[{"name":"Division of Nephrology and"},{"name":"Center for Lung Biology, Department of Medicine and Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryce G.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Division of Nephrology and"},{"name":"Center for Lung Biology, Department of Medicine and Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujiro","family":"Kida","sequence":"additional","affiliation":[{"name":"Division of Nephrology and"},{"name":"Center for Lung Biology, Department of Medicine and Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Ip","sequence":"additional","affiliation":[{"name":"Division of Nephrology and"},{"name":"Center for Lung Biology, Department of Medicine and Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn C.","family":"Davidson","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, and"},{"name":"Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuei-Liong","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Physiology and Medicine, National Taiwan University Hospital, Taipei 100, Taiwan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Lang","sequence":"additional","affiliation":[{"name":"Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229; 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