Renal allograft chronic dysfunction is the main factor influence on the long term survival of renal allograft, and is due to multiple causes. The clinical manifestations are gradually loss of renal allograft function and serum creatinine slowly creeping upward. The risk factors of renal allograft dysfunction include immune factors, such as times of early acute rejection and matching of HLA and protocol of immunosuppression, and non-immune factors such as ischemia/reperfusion injury, delayed graft function, nephrotoxicity of calcineurin inhibitors, hypertension and dyslipidemia, and progressively develop into end stage renal disease. Chronic renal allograft dysfunction morphological appearance as thickening of glomerular basement membrane as double contours sign, thickening of the basement membrane of peritubular capillary, and/or diffuse mononuclear cell infiltration and fibrosis in interstitium and difusse tubular atrophy, and/or thickening of artery intima.
Our study has found that GSK-3β was weakly expressed in normal renal tissue, and was strongly expressed in chronic dysfunction renal allograft tissue, and was stronger in the more severity of pathological changes. The IOD of GSK-3β was higher than that in normal renal tissue, and increasing with the severity of inflammatory infiltration, interstitial fibrosis and tubular atrophy, which suggest that the correlation of GSK-3β expression and interstitial inflammatory infiltration, interstitial fibrosis/tubular atrophy. It was necessary to further study the pathogenic mechanism of GSK-3β in the course of interstitial inflammatory infiltration, interstitial fibrosis and tubular atrophy.
Recent researches have found that the GSK-3β family of serine/threonine kinases extensively existed in the eucaryon, and mainly express in the lung, kidney and brain, and influence on construction, growth, activation and apoptosis of the cells by involving the basic cellular processes such as signal transduction, regulation of insulin, gene transcription and translation. The activation of GSK-3β mainly through phosphorylation of serine-9 near the N-terminus, and is associated to the regulation of signal pathway of Wnt, protein kinase B/Akt and NF-κB. The abnormal activatin of GSK-3β is associated with several kidney diseases, such as diabetic nephropathy, mesangioproliferative glomerulonephritis, lupus nephritis and chronic allograft nephropathy. Recently, several researches revealed that GSK-3β involved in human inflammatory diseases by controling the production of inflammatory factors and involvement into NF-κB signal pathway, and the activation of NF-κB is the center step of inflammatory reaction. Giannopoulou M. et al. found in cultured renal tubular epithelium that hepatocyte growth factor (HGF) has a potent suppressive effect on NFkappaB activation, which was mediated by GSK-3β. HGF can inhibit renal inflammation and proinflammatory chemokine expression by disrupting NF-kB signaling . Adminis- tration of a GSK-3 inhibitor potently suppressed the proinflammatory response in mice receiving lipopolysaccharide and mediated protection from endotoxin shock . Study of Gong and colleagues had proved that GSK-3β was a new marker of chronic renal allograft dysfunction and mediating proinflammatory NF-kB activation and renal inflammation. GSK-3β over expression in the damaged tubular epithelial cells and the magnitude of GSK-3β phosphorylation (p-GSK, inactivation state) was inversely correlated with the degree of injury as assessed by Banff criteria. The higher level of p-GSK expression, the lower level of tubular atrophy and interstitial fibrosis .
Chronic renal allograft dysfunction is an important factor influence on the long term survival of transplant kidney, but the pathogenic mechanism is still not fully interpreted. Infiltration of mononuclear cell (monocyte and lymphocyte) often presents in the renal tissue of chronic dysfunction and relate to endarteritis and interstitial fibrosis. Impairment of renal tubular epithelium and interstitial inflammatory infiltration play an important role in various kidney diseases. Inflammatory factors induce secretion of extracellular matrix by interstitial fibrocyte and result in interstitial fibrosis. In vitro and in vivo experiments shown that GSK-3β involved in inflammatory diseases and inhibition of GSK-3β retarded the progression of these diseases. In the diabetic nephropathy mice experiment model, troglitazone a peroxisome proliferator -activated receptor gamma (PPAR gamma) agonists, ameliorate renal fibrotic lesions through reverse high glucose induced expressions of GSK-3β and inhibition epithelial-mesenchymal transition . In the rats with experimental mesangial proliferative glomerulonephritis, inhibitors of cyclin- dependent kinase (CDK)/GSK-3β were the effective antagonists of proliferating and immunity renal disease . CDK/GSK-3β inhibitors suppress pathogenic proliferation, apoptosis, and inflammation, and promote regeneration of injured tissue in parenchymal renal diseases . Sinha D and his colleague had studied the proximal tubular cells cultured in the absence of growth factors, found that GSK-3β inhibitor might improve the survival of proximal tubular cells. The main mechanism was by activation of Wnt signaling, which promoted the repair of damaged renal parenchyma .
Summary, there is intensive expression of GSK-3β in the renal tissue of the patients with chronic allograft dysfunction, and is associated with inflammatory cell infiltration of interstitium and interstitial fibrosis/tubular atrophy. Further studies are needed to investigate the pathogenic mechanism of GSK-3β expression in the renal tissue of chronic allograft dysfunction. Inhibition the activity of GSK-3β may be a new treatment target of prevention chronic renal allograft dysfunction.