title: Glycogen synthase kinase-3 inhibition attenuates fibroblast activation and development of fibrosis following renal ischemia-reperfusion in mice.
abstract: Glycogen synthase kinase-3β (GSK3β) is a serine/threonine protein kinase that plays an important role in renal tubular injury and regeneration in acute kidney injury. However, its role in the development of renal fibrosis, often a long-term consequence of acute kidney injury, is unknown. Using a mouse model of renal fibrosis induced by ischemia-reperfusion injury, we demonstrate increased GSK3β expression and activity in fibrotic kidneys, and its presence in myofibroblasts in addition to tubular epithelial cells. Pharmacological inhibition of GSK3 using TDZD-8 starting before or after ischemia-reperfusion significantly suppressed renal fibrosis by reducing the myofibroblast population, collagen-1 and fibronectin deposition, inflammatory cytokines, and macrophage infiltration. GSK3 inhibition in vivo reduced TGF-β1, SMAD3 activation and plasminogen activator inhibitor-1 levels. Consistently in vitro, TGF-β1 treatment increased GSK3β expression and GSK3 inhibition abolished TGF-β1-induced SMAD3 activation and α-smooth muscle actin (α-SMA) expression in cultured renal fibroblasts. Importantly, overexpression of constitutively active GSK3β stimulated α-SMA expression even in the absence of TGF-β1 treatment. These results suggest that TGF-β regulates GSK3β, which in turn is important for TGF-β-SMAD3 signaling and fibroblast-to-myofibroblast differentiation. Overall, these studies demonstrate that GSK3 could promote renal fibrosis by activation of TGF-β signaling and the use of GSK3 inhibitors might represent a novel therapeutic approach for progressive renal fibrosis that develops as a consequence of acute kidney injury.
authors.affiliation: The Kidney Institute, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160-3018, USA.
authors.forename: Shailendra P
authors.initials: SP
authors.lastname: Singh
authors.affiliation: The Kidney Institute, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160-3018, USA.
authors.forename: Shixin
authors.initials: S
authors.lastname: Tao
authors.affiliation: The Kidney Institute, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160-3018, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Fields
authors.affiliation: The Kidney Institute, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160-3018, USA.
authors.forename: Sydney
authors.initials: S
authors.lastname: Webb
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.affiliation: The Kidney Institute, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160-3018, USA rrao@kumc.edu.
authors.forename: Reena
authors.initials: R
authors.lastname: Rao
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013830:Thiadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D013830:Thiadiazoles; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Fibrosis; Glycogen synthase kinase-3β; TGF-β1