Glycogen synthase kinase 3beta: a novel marker and modulator of inflammatory injury in chronic renal allograft disease.
One key cell-signaling event central to inflammation in kidney diseases, including chronic renal allograft dysfunction or disease (CRAD), is the activation of NF-kappaB, which controls transcription of numerous proinflammatory mediators. Glycogen synthase kinase (GSK) 3beta is an indispensable element of NF-kappaB activation, however, the exact role of GSK3beta in the pathogenesis of inflammatory kidney diseases like CRAD is uncertain and was examined. Immunohistochemistry staining of GSK3beta 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 GSK3beta activity is regulated by inhibitory phosphorylation of its serine 9 residue, and this occurred in CRAD. Thus, the magnitude of GSK3beta inactivation was inversely correlated with the degree of injury as assessed by Banff criteria. In vitro in cultured human tubular epithelial cells, GSK3beta overexpression augmented, while GSK3beta silencing diminished proinflammatory cellular responses to TNF-alpha stimulation, including NF-kappaB activation and expression of chemokines MCP-1 and RANTES. These inflammatory responses were obliterated by GSK3beta inhibitors. Collectively, GSK3beta plays an important role in mediating proinflammatory NF-kappaB activation and renal inflammation. Suppression of GSK3beta activity might represent a novel therapeutic strategy to treat CRAD.
Gong
R
R
Division of Kidney Disease and Hypertension, Department of Medicine, Brown University School of Medicine, Providence, RI, USA. Rujun_Gong@hotmail.com
Ge
Y
Y
Chen
S
S
Liang
E
E
Esparza
A
A
Sabo
E
E
Yango
A
A
Gohh
R
R
Rifai
A
A
Dworkin
L D
LD
D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D014184:Transplantation, Homologous / Q000009:adverse effects
D015415:Biomarkers; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D016328:NF-kappa B; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3