title: Glycogen synthase kinase-3β promotes cyst expansion in polycystic kidney disease.
abstract: Polycystic kidney diseases (PKDs) are inherited disorders characterized by the formation of fluid filled renal cysts. Elevated cAMP levels in PKDs stimulate progressive cyst enlargement involving cell proliferation and transepithelial fluid secretion often leading to end-stage renal disease. The glycogen synthase kinase-3 (GSK3) family of protein kinases consists of GSK3α and GSK3β isoforms and has a crucial role in multiple cellular signaling pathways. We previously found that GSK3β, a regulator of cell proliferation, is also crucial for cAMP generation and vasopressin-mediated urine concentration by the kidneys. However, the role of GSK3β in the pathogenesis of PKDs is not known. Here we found that GSK3β expression and activity were markedly upregulated and associated with cyst-lining epithelia in the kidneys of mice and humans with PKD. Renal collecting duct-specific gene knockout of GSK3β or pharmacological inhibition of GSK3 effectively slowed down the progression of PKD in mouse models of autosomal recessive or autosomal dominant PKD. GSK3 inactivation inhibited cAMP generation and cell proliferation resulting in reduced cyst expansion, improved renal function, and extended life span. GSK3β inhibition also reduced pERK, c-Myc, and cyclin-D1, known mitogens in proliferation of cystic epithelial cells. Thus, GSK3β has a novel functional role in PKD pathophysiology, and its inhibition may be therapeutically useful to slow down cyst expansion and progression of PKD.
authors: Department of Medicine, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors: Shixin
authors: S
authors: Tao
authors: Department of Medicine, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors: Vijayakumar R
authors: VR
authors: Kakade
authors: Samuel Lunenfeld Research Institute, Mount Sinai Hospital and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors: James R
authors: JR
authors: Woodgett
authors: Department of Medicine, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors: Pankaj
authors: P
authors: Pandey
authors: Department of Medicine, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors: Erin D
authors: ED
authors: Suderman
authors: Department of Medicine, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors: Madhumitha
authors: M
authors: Rajagopal
authors: Department of Medicine, The Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors: Reena
authors: R
authors: Rao
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D003560:Cysts / Q000378:metabolism* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007668:Kidney / Q000201:enzymology; D007685:Kidney Tubules, Collecting / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D007690:Polycystic Kidney Diseases / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D004791:Enzyme Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D013830:Thiadiazoles; D019938:Cyclin D1; D000242:Cyclic AMP; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3
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