title: Fine-tuning of NFκB by glycogen synthase kinase 3β directs the fate of glomerular podocytes upon injury.
abstract: Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) is regulated by a myriad of signaling cascades including glycogen synthase kinase (GSK) 3β and plays a Janus role in podocyte injury. In vitro, lipopolysaccharide (LPS) or adriamycin (ADR) elicited podocyte injury and cytoskeletal disruption, associated with NFκB activation and induced expression of NFκB target molecules, including pro-survival Bcl-xL and podocytopathic mediators like MCP-1, cathepsin L, and B7-1. Broad-range inhibition of NFκB diminished the expression of all NFκB target genes, restored cytoskeleton integrity, but potentiated apoptosis. In contrast, blockade of GSK3β by lithium or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) mitigated the expression of podocytopathic mediators, ameliorated podocyte injury, but barely affected Bcl-xL expression or sensitized apoptosis. Mechanistically, GSK3β was sufficient and essential for RelA/p65 phosphorylation, specifically at serine 467, which specifies the expression of selective NFκB target molecules, including podocytopathic mediators, but not Bcl-xL. In vivo, lithium or TDZD-8 therapy improved podocyte injury and proteinuria in mice treated with LPS or ADR, concomitant with the suppression of podocytopathic mediators, but retained Bcl-xL in glomerulus. Broad-range inhibition of NFκB conferred similar but much weakened antiproteinuric and podoprotective effects accompanied with a blunted glomerular expression of Bcl-xL and marked podocyte apoptosis. Thus, the GSK3β-dictated fine-tuning of NFκB may serve as a novel therapeutic target for podocytopathy.
authors: 1] Department of Nephrology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China [2] Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
authors: Hui
authors: H
authors: Bao
authors: Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
authors: Yan
authors: Y
authors: Ge
authors: Department of Nephrology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors: Ai
authors: A
authors: Peng
authors: Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
authors: Rujun
authors: R
authors: Gong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018122:B7-1 Antigen / Q000378:metabolism; D056668:Cathepsin L / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004317:Doxorubicin; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007678:Kidney Glomerulus; D008070:Lipopolysaccharides; D008094:Lithium / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000139:chemically induced / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D018122:B7-1 Antigen; C494812:Bcl2l1 protein, mouse; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011759:Pyrrolidines; C498144:Rela protein, mouse; D015842:Serine Proteinase Inhibitors; D013830:Thiadiazoles; D013859:Thiocarbamates; D051996:Transcription Factor RelA; D051020:bcl-X Protein; C020972:pyrrolidine dithiocarbamic acid; D014108:Tosylphenylalanyl Chloromethyl Ketone; D004317:Doxorubicin; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D056668:Cathepsin L; C534278:Ctsl protein, mouse
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