title: Activation of glycogen synthase kinase 3β ameliorates diabetes-induced kidney injury.
abstract: Increase in protein synthesis contributes to kidney hypertrophy and matrix protein accumulation in diabetes. We have previously shown that high glucose-induced matrix protein synthesis is associated with inactivation of glycogen synthase kinase 3β (GSK3β) in renal cells and in the kidneys of diabetic mice. We tested whether activation of GSK3β by sodium nitroprusside (SNP) mitigates kidney injury in diabetes. Studies in kidney-proximal tubular epithelial cells showed that SNP abrogated high glucose-induced laminin increment by stimulating GSK3β and inhibiting Akt, mTORC1, and events in mRNA translation regulated by mTORC1 and ERK. NONOate, an NO donor, also activated GSK3β, indicating that NO may mediate SNP stimulation of GSK3β. SNP administered for 3 weeks to mice with streptozotocin-induced type 1 diabetes ameliorated kidney hypertrophy, accumulation of matrix proteins, and albuminuria without changing blood glucose levels. Signaling studies showed that diabetes caused inactivation of GSK3β by activation of Src, Pyk2, Akt, and ERK; GSK3β inhibition activated mTORC1 and downstream events in mRNA translation in the kidney cortex. These reactions were abrogated by SNP. We conclude that activation of GSK3β by SNP ameliorates kidney injury induced by diabetes.
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78245 and Medical Service, South Texas Veterans Health Care System, San Antonio, Texas 78229.
authors.forename: Meenalakshmi M
authors.initials: MM
authors.lastname: Mariappan
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78245 and.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Prasad
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78245 and.
authors.forename: Kristin
authors.initials: K
authors.lastname: D'Silva
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78245 and.
authors.forename: Esteban
authors.initials: E
authors.lastname: Cedillo
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78245 and.
authors.forename: Kavithalakshmi
authors.initials: K
authors.lastname: Sataranatarajan
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78245 and.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Barnes
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78245 and Medical Service, South Texas Veterans Health Care System, San Antonio, Texas 78229 the Geriatric Research, Education, and Clinical Center and.
authors.forename: Goutam Ghosh
authors.initials: GG
authors.lastname: Choudhury
authors.affiliation: From the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78245 and Medical Service, South Texas Veterans Health Care System, San Antonio, Texas 78229 kasinath@uthscsa.edu.
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
mesh_terms: D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D002461:Cell Line, Transformed; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000517:prevention & control*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006984:Hypertrophy / Q000517:prevention & control; D015151:Immunoblotting; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D007797:Laminin; D046912:Multiprotein Complexes; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3
keywords: Cell Signaling; Diabetic Nephropathy; Eukaryotic Translation Initiation; Extracellular Matrix Protein; Glycogen Synthase Kinase 3 (GSK-3); Kidney; Kidney Hypertrophy; Mammalian Target of Rapamycin (mTOR); Sodium Nitroprusside; Type 1 Diabetes