{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T20:10:43Z","timestamp":1786133443594,"version":"build-2736575974"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2018,12]]},"abstract":"\n Background<\/jats:title>\n The death of epithelial cells in the proximal tubules is thought to be the primary cause of AKI, but epithelial cells that survive kidney injury have a remarkable ability to proliferate. Because proximal tubular epithelial cells play a predominant role in kidney regeneration after damage, a potential approach to treat AKI is to discover regenerative therapeutics capable of stimulating proliferation of these cells.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We conducted a high-throughput phenotypic screen using 1902 biologically active compounds to identify new molecules that promote proliferation of primary human proximal tubular epithelial cells\n in vitro<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The primary screen identified 129 compounds that stimulated tubular epithelial cell proliferation. A secondary screen against these compounds over a range of four doses confirmed that eight resulted in a significant increase in cell number and incorporation of the modified thymidine analog EdU (indicating actively proliferating cells), compared with control conditions. These eight compounds also stimulated tubular cell proliferation\n in vitro<\/jats:italic>\n after damage induced by hypoxia, cadmium chloride, cyclosporin A, or polymyxin B. ID-8, an inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), was the top candidate identified as having a robust proproliferative effect in two-dimensional culture models as well as a microphysiologic, three-dimensional cell culture system. Target engagement and genetic knockdown studies and RNA sequencing confirmed binding of ID-8 to DYRK1A and upregulation of cyclins and other cell cycle regulators, leading to epithelial cell proliferation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n We have identified a potential first-in-class compound that stimulates human kidney tubular epithelial cell proliferation after acute damage\n in vitro<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2018040392","type":"journal-article","created":{"date-parts":[[2018,10,25]],"date-time":"2018-10-25T14:29:26Z","timestamp":1540477766000},"page":"2820-2833","source":"Crossref","is-referenced-by-count":12,"title":["A High-Throughput Screen Identifies DYRK1A Inhibitor ID-8 that Stimulates Human Kidney Tubular Epithelial Cell Proliferation"],"prefix":"10.1681","volume":"29","author":[{"given":"Maria B.","family":"Monteiro","sequence":"first","affiliation":[{"name":"Harvard Program in Therapeutic Science, Harvard Medical School Laboratory of Systems Pharmacology, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Ramm","sequence":"additional","affiliation":[{"name":"Harvard Program in Therapeutic Science, Harvard Medical School Laboratory of Systems Pharmacology, Boston, Massachusetts;"},{"name":"Renal Division, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidya","family":"Chandrasekaran","sequence":"additional","affiliation":[{"name":"Harvard Program in Therapeutic Science, Harvard Medical School Laboratory of Systems Pharmacology, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Boswell","sequence":"additional","affiliation":[{"name":"Harvard Program in Therapeutic Science, Harvard Medical School Laboratory of Systems Pharmacology, Boston, Massachusetts;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elijah J.","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, University of Washington, Seattle, Washington; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin A.","family":"Lidberg","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, University of Washington, Seattle, Washington; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward J.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, University of Washington, Seattle, Washington; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishal S.","family":"Vaidya","sequence":"additional","affiliation":[{"name":"Harvard Program in Therapeutic Science, Harvard Medical School Laboratory of Systems Pharmacology, Boston, Massachusetts;"},{"name":"Renal Division, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts;"},{"name":"Department of Environmental Health, Harvard T.H. 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