These findings suggest that HGF can retard progression of chronic renal disease even after injury is already established, primarily by promoting matrix degradation.
One key cell-signaling event central to inflammation in kidney diseases, including chronic renal allograft dysfunction or disease (CRAD), is the activation of NF-j B, which controls transcription of numerous proinflammatory mediators. Glycogen synthase kinase (GSK) 3b is an indispensable element of NF-j B activation, however, the exact role of GSK3b in the pathogenesis of inflammatory kidney diseases like CRAD is uncertain and was examined. Immunohistochemistry staining of GSK3b 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 GSK3b activity is regulated by inhibitory phosphorylation of its serine 9 residue, and this occurred in CRAD. Thus, the magnitude of GSK3b inactivation was inversely correlated with the degree of injury as assessed by Banff criteria. In vitro in cultured human tubular epithelial cells, GSK3b overexpression augmented, while GSK3b silencing diminished proinflammatory cellular responses to TNF-a stimulation, including NF-j B activation and expression of chemokines MCP-1 and RANTES. These inflammatory responses were obliterated by GSK3b inhibitors. Collectively, GSK3b plays an important role in mediating proinflammatory NF-j B activation and renal inflammation. Suppression of GSK3b activity might represent a novel therapeutic strategy to treat CRAD.
Clinical episodes of IgA nephropathy coincide recurrently with microbial infections. Cytokines produced during such infections may play a role in the pathogenesis of IgA-associated glomerulonephritis. To test this hypothesis, we examined the influence of passively administered proinflammatory cytokines (IL-1, IFN-gamma and IL-6) on the development of glomerulonephritis in an experimental model of IgA nephropathy. Glomerular IgA immune deposits were induced in mice by administration of IgA anti-phosphorylcholine (PC) with either a PC-containing carbohydrate antigen of Pneumococcal C polysaccharide (PnC) or a protein antigen of PC-conjugated bovine serum albumin (PC-BSA). The effect of IL-1 on the IgA-PC-BSA induced glomerular changes resulted in an increase of mesangial hypercellularity that was associated with mild proteinuria and hematuria. Mice treated with IL-1 and IgA-PnC developed diffuse proliferative glomerulonephritis with proteinuria and hematuria. In contrast, IL-6 treatment with IgA-PC-BSA of IgA-PnC failed to exert any significant renal effect. The combination of IL-6 and IL-1, however, intensified the mesangial hypercellularity of the IgA-PC-BSA, and induced severe proliferative glomerulonephritis with inflammatory monocytes and neutrophils infiltrates in the IgA-PnC treated mice. These glomerular changes were also accompanied by increased proteinuria and hematuria. Similarly, the combination of IFN with IL-1 produced histologic changes and compromised renal function more than IFN or IL-1 exerted independently. These results suggest that extrarenal cytokines influence the renal response to IgA immune deposits. We also conclude that a synergy of multiple cytokines and nephritogenic antigens immobilized in glomerular IgA immune deposits may lead to rapid progression of IgA-associated glomerulonephritis.
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