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A High-Throughput Screen Identifies DYRK1A Inhibitor ID-8 that Stimulates Human Kidney Tubular Epithelial Cell Proliferation.
- Source :
-
Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2018 Dec; Vol. 29 (12), pp. 2820-2833. Date of Electronic Publication: 2018 Oct 25. - Publication Year :
- 2018
-
Abstract
- Background: 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.<br />Methods: 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 in vitro .<br />Results: 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 in vitro 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.<br />Conclusions: We have identified a potential first-in-class compound that stimulates human kidney tubular epithelial cell proliferation after acute damage in vitro .<br /> (Copyright © 2018 by the American Society of Nephrology.)
- Subjects :
- Acute Kidney Injury drug therapy
Cell Culture Techniques methods
Cell Cycle drug effects
Cell Cycle genetics
Cell Proliferation drug effects
Cell Proliferation genetics
Cells, Cultured
Drug Discovery
Drug Evaluation, Preclinical
Epithelial Cells cytology
Epithelial Cells drug effects
Epithelial Cells enzymology
High-Throughput Screening Assays
Humans
Kidney Tubules cytology
Kidney Tubules enzymology
Protein Serine-Threonine Kinases metabolism
Protein-Tyrosine Kinases metabolism
Regenerative Medicine
Dyrk Kinases
Kidney Tubules drug effects
Protein Kinase Inhibitors pharmacology
Protein Serine-Threonine Kinases antagonists & inhibitors
Protein-Tyrosine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1533-3450
- Volume :
- 29
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of the American Society of Nephrology : JASN
- Publication Type :
- Academic Journal
- Accession number :
- 30361326
- Full Text :
- https://doi.org/10.1681/ASN.2018040392