IgA肾病患者肾组织中丝裂素活化蛋白活化与肾小管上皮细胞转分化的关系

Relationship of mitogen-activated protein kinases activation with transdifferentiation of renal tubular epithelial cells in patients with IgA nephropathy

目的 检测IgA肾病患者肾小管上皮细胞中丝裂素活化蛋白激酶 (MAPK)不同亚类蛋白质表达及磷酸化水平的变化 ,初步探讨MAPK各亚类在体内对肾小管上皮细胞转分化的调控作用。方法 36例住院IgA肾病患者的肾活检标本 ,分为轻度系膜增生组、局灶增生组和增生硬化组。采用普通病理染色和免疫组织化学技术 ,观察各组肾组织中肾小管和间质的病理改变、肾小管间质损伤指数、增殖细胞核抗原 (PCNA)和纤连蛋白 (FN)在肾小管、α 平滑肌肌动蛋白 (α SMA)在肾小管和间质表达的变化 ,并应用非磷酸化和磷酸化激酶的特异抗体检测肾组织内MAPK(包括ERK、JNK和p38)的表达及活化情况。结果 随着肾小球病变程度的加重 ,肾小管间质损伤指数增加。肾小管上皮细胞的PCNA阳性率逐渐增高 ;其中增生硬化组的PCNA阳性率是正常对照组的 2 38倍 (P <0 0 1) ,α SMA表达阳性的肾小管上皮细胞明显增多 ,局灶增生组和增生硬化组的肾小管α SMA表达阳性率均显著增高 (P <0 0 5 )。FN在肾间质的表达增加 ,α SMA表达阳性率与FN表达阳性率和肾间质纤维化程度呈正相关。正常人肾组织中MAPK各亚类均有基础表达 ,IgA肾病患者肾组织中MAPK各亚类的表达部位与正常人相似 ,肾小管ERK和JNK活化程度随肾小球病变程度的加重而逐渐增加 。

Objective To investigate the expression patterns of MAPK family (including ERK, JNK and p38) and to analyze the effects of MAPKs on renal tubular epithelial cells (RTEC) transdifferentiation in vivo.Methods Renal biopsy specimen were collected from 36 patients with IgA nephropathy (IgAN), which were divided into mild proliferation group (MP), focal proliferation group(FP) and proliferation sclerosis group(PS) according to the glomerular lesions. Renal tubulointerstitial lesion score was assessed. Positive tubules of PCNA, FN, ɑ SMA, MAPK subtypes expression and phosphorylation in renal tubules were detected by immunohistochemistry staining combined with semi quantitived method.A correlation analysis was made.Results In the MP, FP and PS groups of IgAN, the score of tubulointerstitial lesion, the positive stained tubule of PCNA, ɑ SMA and FN expression were more abundant with the severity of glomerular injury. The expression of ɑ SMA in tubule was correlated closely to FN expression and the score of interstitial fibrosis. Distribution of all subtypes of MAPK in renal tissue was no different between IgAN and normal subjects. With the severity of glomerular disease, positive tubules expressed P ERK or P JNK increased gradually, especially in PS group, in which expression of P ERK was 3 fold and P JNK was 1 6 fold compared to control ( P <0 05). Expression of JNK protein in tubule was enhanced in PS group. Expression of P p38 had no change in different groups. P ERK positive tubules correlated to FN expression.Conclusion ERK and JNK are strongly expressed and activated in renal tubules in patients with IgAN. It seems that JNK activation is a critical signal to regulate RTEC transdifferentiation, but ERK activation may play an indirect role on this process.