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Glycogen Synthase Kinase 3β: A Novel Marker and Modulator of Inflammatory Injury in Chronic Renal Allograft Disease
Author(s) -
Gong R.,
Ge Y.,
Chen S.,
Liang E.,
Esparza A.,
Sabo E.,
Yango A.,
Gohh R.,
Rifai A.,
Dworkin L. D.
Publication year - 2008
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2008.02319.x
Subject(s) - proinflammatory cytokine , gsk 3 , inflammation , gsk3b , medicine , chemokine , cancer research , immunology , kinase , biology , microbiology and biotechnology
One key cell‐signaling event central to inflammation in kidney diseases, including chronic renal allograft dysfunction or disease (CRAD), is the activation of NF‐κB, which controls transcription of numerous proinflammatory mediators. Glycogen synthase kinase (GSK) 3β is an indispensable element of NF‐κB activation, however, the exact role of GSK3β in the pathogenesis of inflammatory kidney diseases like CRAD is uncertain and was examined. Immunohistochemistry staining of GSK3β was weak in normal kidneys, but was markedly induced in inflamed allograft kidneys, with prominent cytoplasmic staining of tubular cells in areas of inflammation. Net GSK3β activity is regulated by inhibitory phosphorylation of its serine 9 residue, and this occurred in CRAD. Thus, the magnitude of GSK3β inactivation was inversely correlated with the degree of injury as assessed by Banff criteria. In vitro in cultured human tubular epithelial cells, GSK3β overexpression augmented, while GSK3β silencing diminished proinflammatory cellular responses to TNF‐α stimulation, including NF‐κB activation and expression of chemokines MCP‐1 and RANTES. These inflammatory responses were obliterated by GSK3β inhibitors. Collectively, GSK3β plays an important role in mediating proinflammatory NF‐κB activation and renal inflammation. Suppression of GSK3β activity might represent a novel therapeutic strategy to treat CRAD.