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The Study of Molecular Pathomechanism on the Role of GSK-3β Signaling Pathway and Its Significance in Chronic Rneal Allograft Dysfunction

Author: WangBaoYao
Tutor: ZuoQiang
School: Southern Medical University,
Course: Department of Urology
Keywords: Chronic allograft renal dysfunction kidney transplantation GSK-3β Interstitial fibrosis and tubular atrophy Inflammatory cell infiltration
CLC: R699.2
Type: Master's thesis
Year: 2012
Downloads: 51
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Abstract


Reserch background:Kidney transplantation is the optimal renal replacement therapy for the patients with end stage renal disease (ESRD). As the application of more new effective immunodepressants and the development of transplant technique, the incidence of acute rejection is obviously decreasing in the early stage post transplantation, but the long term survival of renal allografts is still a challenge of clinical medicine. Recent researches have found that chronic renal allograft dysfunction is the main factor influence on the long term survival of renal allograft. The main clinical manifestations of chronic renal allograft dysfunction(CRAD) are serum level of creatinine is slowly creeping upward company with proteinuria and hypertension, and progression into ESRD need kidney transplantation again or on maintenance dialysis. Data from Leicester show that, despite a1-year graft survival of about90percent, there is a gradual attrition of4~5percent of graft loss per year, leading to5-and10-year allograft survival rates of approximately70and50percent respectively. The main pathogenic course of chronic renal allograft dysfunction is glomerulosclerosis, vasculopathy, atrophy of tubule and chronic renal interstitial fibrosis. All there pathogenic changes are associated with lymphocyte, plasmocyte and mastocyte infiltration in the renal tissue. Researches have proved that chronic inflammatory was the key pathogenic course of nephron loss in various of kidney disease, including chronic renal allograft dysfunction.More recent, researches discovered that GSK-3β mediated chronic inflammatory related to deterioration of renal allograft function, but the mechanism has not been full interpreted. Glycogen synthase kinase-3β(GSK-3β) is a serine/threonine kinase, glycogen synthase kinase regulate various cellular responses, such as:cell growth, differentiation, Apoptosis and inflammation. The enzyme is a key regulator of numerous signalling pathways, including cellular responses to Wnt, phosphatidylinositol-3-kinase (PI3K) and NF-κB and is involved in a wide range of cellular processes, ranging from glycogen metabolism to cell cycle regulation and proliferation. Glycogen synthase kinase-3β (GSK-3β) is a ubiquitous serine-threonine protein kinase involved in glycogen metabolism, cell membrane to nucleus signal transducting, gene transcription and translation, protein translation, cytoskeletal organization, cell cycle regulation, and apoptosis. GSK-3β plays an important role in the pathological process of various human diseases (such as Alzheimer’s disease, bipolar disorder, cancer). GSK-3β was initially described for its function to inhibit glycogen synthesis through phosphorylation of glycogen synthase, The phosphorylation sites that lead to the inactivation of GSK-3have been identified as Ser9for GSK-3β; GSK-3β negatively regulates downstream signaling mechanisms, inactivation of GSK-3β in fact stimulates many cellular functions by removing the negative constraint imposed by GSK-3β。Recents studied showed that GSK-3β mediate proinflammatory nuclear factor κB(NF-κB) activation and NF-κB expression of chemokines. In recent years, some research revealed GSK-3β participants in experimental models of inflammation diseases, such as acute renal failure, diabetic nephropathy, chronic allograft nephropathy. In this study, we mainly detected the expression of GSK-3β in the tissue of renal allograft, and analyzed the relationship between the expression of GSK-3P and inflammatory cell infiltration in renal interstitium, interstitial fibrosis and tubule atrophy. The role of GSK-3β in chronic allograft dysfunction was discussed.ObjectiveTo study the histopathologic characteristics of renal allograft tissues with chronic renal allograft dysfunction(CRAD).The functions of the GSK-3beta in the renal fibrosis course of CRAD, and to analyze the mechanisms of renal fibrosis of CRAD for presenting the direction and theoretic evidences to treat the disease of CRAD.Methods Clinical dataThe renal biopsy samples were collected from kidney transplant patients with proteinuria and elevated serum creatine from January,2007to December2009in Guilin181hospital. In the28cases consistented with clinical diagnosis of chronic allograft dysfunction,21cases were males (age45±10years) and7cases were females (age42±9years). The durations after kidney transplantation were1-9years (mean3.5years) and the mean levels of serum creatine were206±122μmol/L. The triple immunosuppressant protocols were cyclosporine+mycophenolate mofetil+prednisone in18patients and tacrolimus+mycophenolate mofetil+prednisone in9patients and sirolimus+.mycophenolate mofetil+prednisone in1patient. Before renal biopsy, color Doppler supersonic detection in renal allograft and serum drug levels were performed to exclude acute rejection, nephrotoxicity of immunosuppressant, obstruction/backstreaming of ureter, thrombosis or embolism in renal arteries or veins and other diseases. The donors and recipients were matching in ABO blood type, and two or more matching in HLA, and the results of lymphocytotoxicity test were less than10%, and the results of panel reaction antibody (PRA) were negative. The renal samples of5cases of control were collected from routine donor renal biopsy before transplantation, which pathologic manifestation was normal. All the33samples were made paraffin blocks, then were stained by HE, PASM, Masson methods and detected IgG、IgA、IgM、Clq or C4c with immunohistochemisty.Pathologic diagnosisThe degree of inflammatory cell infiltration in tubulointerstitial was described as mild, midrange and severe. There were few and scatter inflammatory cell infiltration in10-25%of parenchyma was defined as mild; inflammatory cell infiltration in26-50%of parenchyma was defined as midrange; inflammatory cell infiltration in>50%of parenchyma was defined as serve.Degree of interstitial fibrosis and tubular atrophy:IF/TA-Ⅰ, as mild interstitial fibrosis and tubular atrophy (<25%of cortical area); IF/TA-Ⅱ, as moderate interstitial fibrosis and tubular atrophy (26-50%of cortical area); IF/TA-Ⅲ, as Severe interstitial fibrosis and tubular atrophy/loss (>50%of cortical area).Image analysisImages were acquired using a Leica DMR-X microscope coupled to a Leica DC500digital camera (Leica, Wetzlar, Germany), using the image analysis system Quantimet Q550(Leica Imaging Systems). Ten randomly selected discontinuous fields (400x) per kidney were evaluated, including tubulointerstitial in renal cortex, medulla and the conjunction region,(but not including glomulular and vessels). More than60tubulars in each biopsy section. The positive area was yellowly stained and Image-Pro Plus software was used to quantify the integrated optical density. The ratio of positive area to total tubulointerstitial area (not including the area of tubular lumina) presented the relative amount of the substance expression in tubuloinstitial.Statistic analysisResults are expressed as means±SD. Statistical analysis was performed using SPSS13.0(SPSS, Chicago, IL). Measurement data was analyzed with one way ANOVA, after the test of homogeneity of variances, one way ANOVA was applied to analyze the data with homogeneitic variances and LSD used for two-two comparison. And Welch Test was applied to analyze the data with heterogeneity of variances and Dunnett’T3used for two-two comparison, and the relationship was analyzed with linear correlation (Pearson). Statistic significance was set at P<0.05level.Results:1.Histological manifestationThe main histological manifestation of renal allograft in the28cases of chronic renal allograft dysfunction as:interstitial fibrosis and tubular atrophy accompany with infiltration of inflammatory cells including lymphocyte and monocyte, enlarge of some tubular lumens, thickening of glomerular basement membrane as double trace sign and focal segmental glomerulosclerosis, thickening of artery intimae. Discrepancy to the presentation of acute rejection, nephrotoxicity of immunosuppressant and obstruction uropathy/reflux nephropathy.2.The expression of GSK-3β in renal tissueThere was weak expression of GSK-3β in the cytoplasm of tubular epithelia cell in normal renal tissue. However, in the dysfunction renal allograft tissue, there were strong cytoplasm GSK-3β expression in tubular epithelia cell, and GSK-3β expression became stronger along with the increasing of the grade of either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft tissue.(Shown in table1, table2and figure1, figure2) 3.The relationship of GSK-3β expression and inflammatory infiltration, interstitial fibrosis and tubular atrophyStatistical analysis showed that the expression levels of GSK-3β in the renal tubule and interstitium of CRAD patients were significantly increased, compared to normal controls(P<0.001); In the renal tissue of chronic renal allograft dysfunction, the integrated optical density (IOD) was higher than normal renal tissue by analysis with Image-Pro software, there might be a positive correlation between either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy and high GSK-3β expression in renal allograft tissue (r=0.688and0.584, p<0.05).(Figure3,4).Conclusions:1. The major histopathological disprders of Chronic allograft renal dysfunction are characterized by inflammatory infiltration and interstitial fibrosis and tubular atrophy.2. The expression level of the GSK-3β was significantly increased in the renal allograft tissue of recipients with chronic allograft dysfunction, and GSK-3β expression became stronger along with the increasing of the grade of either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft tissue, It is suggested that increased GSK-3β might be related to the mechanism of the pathological disorders3. There might be a positive correlation between either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy and high GSK-3expression in renal allograft tissue, it is suggested that GSK-3β might be involved in the pathogenesis of CRAD by regulation the inflammatory cell infiltration.

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CLC: > Medicine, health > Surgery > Urology ( urinary and reproductive system diseases) > Urinary tract and male reproductive system surgery > Kidney surgery
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