Glycogen synthase kinase 3β:: 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-kappa B, which controls transcription of numerous proinflammatory mediators. Glycogen synthase kinase (GSK) 3 beta is an indispensable element of NF-kappa B activation, however, the exact role of GSK3 beta in the pathogenesis of inflammatory kidney diseases like CRAD is uncertain and was examined. Immunohistochemistry staining of GSK3 beta 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 GSK3 beta activity is regulated by inhibitory phosphorylation of its serine 9 residue, and this occurred in CRAD. Thus, the magnitude of GSK3 beta inactivation was inversely correlated with the degree of injury as assessed by Banff criteria. In vitro in cultured human tubular epithelial cells, GSK3 beta overexpression augmented, while GSK3 beta silencing diminished proinflammatory cellular responses to TNF-alpha stimulation, including NF-kappa B activation and expression of chemokines MCP-1 and RANTES. These inflammatory responses were obliterated by GSK3 beta inhibitors. Collectively, GSK3 beta plays an important role in mediating proinflammatory NF-kappa B activation and renal inflammation. Suppression of GSK3 beta activity might represent a novel therapeutic strategy to treat CRAD.