肾小管上皮细胞转分化在肾间质纤维化中的研究进展

肾小管上皮细胞转分化在肾间质纤维化发生中起到重要作用,其转化条件和机制已成为当今学者研究的热点。本文就肾小管上皮细胞转分化的概念、标志、发生机制、步骤及药物对其影响进行综述。     

肾小管上皮细胞-间充质细胞转分化在肾间质纤维化中的作用

慢性肾脏疾病的进展是一个不可逆的过程，最终导致终末期肾功能衰竭。肾间质纤维化几乎是所有肾脏疾病进展到终末期肾功能衰竭的共同病理途径。本文综述近几年关于肾小管上皮细胞-间充质细胞转分化(EMT)在肾间质纤维化中的病理学意义，分子机制及治疗干预的研究。其中转化生长因子-betal(TGF—β1)是上皮-间质细胞转分化重要的诱导荆，完整的TGF-β1／Smad信号传导途径介导EMT。整合索连接酶ILK是诱导EMT的关键调节因子。     

肾小管上皮细胞-间充质细胞转分化在肾间质纤维化中的作用

慢性肾脏疾病的进展是一个不可逆的过程,最终导致终末期肾功能衰竭。肾间质纤维化几乎是所有肾脏疾病进展到终末期肾功能衰竭的共同病理途径。本文综述近几年关于肾小管上皮细胞-间充质细胞转分化(EMT)在肾间质纤维化中的病理学意义,分子机制及治疗干预的研究。其中转化生长因子-beta1(TGF-β1)是上皮-间充质细胞转分化重要的诱导剂,完整的TGF-β1/Smad信号传导途径介导EMT。整合素连接酶ILK是诱导EMT的关键调节因子。     

肾小管上皮细胞转分化在肾间质纤维化过程中的作用及其调控机制研究进展

肾小管上皮细胞转分化是肾间质纤维化的重要发病机制之一,TGF-β可促进肾小管上皮细胞转分化从而促进肾间质纤维化的形成,而BMP7则起抑制作用,最新发现的一种新型蛋白KCP可能通过增强BMP7与其受体的结合能力而发挥抗肾间质纤维化作用.     

肾小管上皮细胞转分化在肾间质纤维化过程中的作用及其调控机制研究进展

肾小管上皮细胞转分化是肾间质纤维化的重要发病机制之一,TGF-β可促进肾小管上皮细胞转分化从而促进肾间质纤维化的形成,而BMP7则起抑制作用,最新发现的一种新型蛋白KCP可能通过增强BMP7与其受体的结合能力而发挥抗肾间质纤维化作用。     

肾小管间质纤维化的发生机理

肾间质纤维化对机体的影响不仅看纤维化的范围，还应看是否有细胞因子，特别是纤维化特异蛋白1的存在；肾间质纤维化发生与肾小管上皮转分化、多种细胞、细胞因子、血管紧张素Ⅱ、缺血缺氧等有关。过去认为基质金属蛋白酶降解细胞外基质，现发现有些基质金属蛋白酶促进肾纤维化。     

肾小管间质纤维化的发生机理

肾间质纤维化对机体的影响不仅看纤维化的范围,还应看是否有细胞因子,特别是纤维化特异蛋白1的存在;肾间质纤维化发生与肾小管上皮转分化、多种细胞、细胞因子、血管紧张素Ⅱ、缺血缺氧等有关。过去认为基质金属蛋白酶降解细胞外基质,现发现有些基质金属蛋白酶促进肾纤维化。     

肾间质纤维化的防治进展

研究表明,肾间质损伤的严重程度与慢性肾功能不全、肾脏纤维化密切相关.因此,防治肾间质纤维化已成为近年肾脏病研究领域的热点之一.本文主要从拮抗肾素-血管紧张素-醛固酮系统作用,针对致纤维化细胞因子的防治策略及基因治疗等方面对肾间质纤维化防治的研究进展作一综述.     

肾小管上皮细胞转分化在肾间质纤维化中的作用

肾间质纤维化（ｒｅｎａｌｉｎｔｅｒｓｔｉｔｉａｌｆｉｂｒｏｓｉｓ，ＲＩＦ）几乎是所有各种肾脏疾病进展到终末期肾功能衰竭的共同途径。Ｒｉｓｄｏｎ［１］、Ｓｃｈａｉｎｕｃｋ［２］、Ｓｔｒｉｋｅｒ［３］等对人类疾病中的肾脏病理性改变及试验动物肾小球损害模型进行的大量研究表明，各种慢性肾小球疾病病人的肾小球滤过率（ＧＦＲ）下降率与肾小管萎缩之间存在着显著的正相关。Ｂｏｈｌｅ［４］等分析了大量病人的肾活检标本，又一次发现间质炎症细胞浸润的程度而非小球中炎症细胞的浸润程度与肾小球疾病的ＧＦＲ下降相关［５］。…     

肾间质纤维化的防治进展

研究表明,肾间质损伤的严重程度与慢性肾功能不全、肾脏纤维化密切相关。因此,防治肾间质纤维化已成为近年肾脏病研究领域的热点之一。本文主要从拮抗肾素-血管紧张素-醛固酮系统作用,针对致纤维化细胞因子的防治策略及基因治疗等方面对肾间质纤维化防治的研究进展作一综述。     

Epithelial-mesenchymal transition and its implications for the development of renal tubulointerstitial fibrosis

Despite a lot of research efforts, the origin of renal fibroblasts is still matter of debate. Epithelial-mesenchymal transition (EMT) of tubular epithelial cells could be at least one of the mechanisms by which renal fibroblasts are generated. Every kind of renal injury is potentially able to induce renal tubular cells to go through the various steps of EMT and generate fibroblasts, as it has been demonstrated by experimental models, in vitro experiments, and renal biopsy studies. It means that, if EMT is a common process of progression of renal failure, further studies and a better understanding of this process can lead us to envisage specific treatments to counteract the progression of renal disease.     

Epithelial-mesenchymal transition of the renal graft

About 40 % of renal graft losses over 10 years in Europe are caused by fibrosis. To explain the origin of interstitial fibroblasts, the epithelial-mesenchymal transition (EMT) theory has been recently ventured : under the effect of an aggression, tubular epithelial cells may change into fibroblasts, cross over the basal membrane, and join interstitium. This innovative hypothesis has been confirmed by the finding of a "fibroblast-specific" protein FSP-1 in the tubular epithelium, then by the detection of fibroblast-like FSP-1 expressing cells in the proximal tubule by confocal microscopy in a transgenic murine model in which fibrosis has been induced. In the renal graft, EMT markers such as FSP-1 and vimentin, have been detected in tubular epithelium in case of chronic allograft nephropathy, correlatively to the loss of expression of epithelial markers. The expression of EMT markers takes place very early, in the first months post-transplantation, in transplant patients whose renal function is not yet impaired, suggesting the existence of a patho-physiological link between EMT markers expression and graft fibrosis development.     

缺氧条件下大鼠肾小管上皮细胞的离体培养及相关检测

目的 探讨缺氧条件下离体培养的肾小管上皮细胞中纤维化相关标记物结缔组织生长因子(CTGF)表达的变化,以及缺氧导致肾小管上皮细胞向间充质细胞转化(EMT)的可能性.方法采用无糖培养基在无氧环境下培养大鼠肾小管上皮细胞(NRK-52E细胞)4 h,恢复含氧环境后再分别培养6、12、24、48和72 h.用实时定量聚合酶链反应和蛋白质印迹测定各时段细胞中CTGF mRNA和CTGF表达的变化.共聚焦显微镜下观察细胞形态变化.对细胞骨架蛋白--多聚体纤维状肌动蛋白(F-actin)进行标记染色,检测缺氧对其的影响.结果 缺氧后NRK-52E细胞骨架蛋白F-actin的表达增加;NRK-52E细胞的形态由立方上皮向肌纤维母细胞转变;缺氧后,细胞中CTGF mRNA和CTGF的表达明显增高,在恢复含氧环境培养48 h时达到高峰,CTGF mRNA值为29.33±0.21,CTGF的吸光度比值为1.30±0.02.结论缺氧可导致大鼠肾小管上皮细胞中CTGF的表达增加,诱导NRK- 52E细胞发生EMT,CTGF可能是NRK-52E细胞发生EMT和纤维化的关键分子.

Abstract：

Objective To explore whether anoxia can induce expression changes in connective tissue growth factor(CTGF)in renal tubular epithelial cells(TECs)and epithelial-mesenchymal transition of TECs.Methods Rat renal TECs(NRK-52E)anoxia models were established.NRK-52E cells were exposed to anoxia for 4 h.The real-time RT-PCR,Western blotting,immunohistochemical staining were used to detect the expression of CTGF at 6,12,24,48,and 72 h in NRK-52E cells.Morphological changes and cytoskeleton remodeling in NRK-52E cells under anoxia were examined by a laser confocal microscope and BODIPYFL staining respectively.Results Under anoxia,NRK-52E cells became round,enlarged and cytoskeleton was remodeled.The expression levels of CTGF mRNA and protein were up-regulated at 6 h,reached their peak at 48 h:the expression of CTGF mRNA protein was 29.33±0.21 and 1.30±0.02 respectively.Under anoxia,NRK-52E cells underwent an epithelial-mesenchymal transition process,including cytoskeleton remodeling,and morphological changes.Conclusion Anoxia can change the expression of CTGF and other fibrosis-associated genes in NRK-52E cells,and CTGF played an important role in fibrosis process and epithelial-mesenchymal transition development in NRK-52E cells.     

肾间质纤维化的研究进展

各种病因导致的慢性、进展性肾脏疾病的最终归宿是肾间质纤维化(renal-interstrial fibrosis,RIF),大量的研究表明RIF是各种细胞、细胞因子、炎症因子、炎症介质等诸多因素相互作用,导致细胞外基质(extracellular matrix,ECM)代谢失衡,在间质异常积聚所致.因此,对RIF的深入研究,将有助于揭示RIF发生与发展的规律.从而找出相应的治疗对策.     

Myofibroblast involvement in renal interstitial fibrosis

Summary: Interstitial fibrosis is a final common pathway for many, if not all forms of end-stage renal disease. Although the kidney contains several cell types that are capable of collagen biosynthesis, most in vitro and in vivo studies suggest that fibroblasts generate the principal interstitial matrix collagens. Recent studies have defined a role for myofibroblasts (cells with features of both fibroblasts and smooth muscle cells) in progressive renal interstitial fibrosis. Renal myofibroblasts are hyperproliferative and up-regulated matrix producers, consistent with them being 'activated' fibroblasts. Interstitial myofibroblasts also share a number of anatomical, phenotypic and biosynthetic features with the glomerular mesangial cell. the interstitium consists of a complex mixture of inflammatory and fibrogenic mediators. the fibroblast response to this microenvironment includes chemotaxis, proliferation and increased synthetic activity. However, the derivation and fate of the fibroblast/myofibroblast during scarring remains unclear, with migration, proliferation, differentiation and cell death all likely to determine cell number.     

Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies

BACKGROUND: In recent studies performed on cultured cells and experimental nephropathies, it has been hypothesized that tubular epithelial cells (TEC), via epithelial-mesenchymal transformation (EMT), can become collagen-producing cells. According to this theory, they should proceed through several activating steps, such as proliferation and phenotype changes, to eventually synthesize extracellular matrix (ECM). METHODS: To evaluate whether EMT operates in human TECs, 133 renal biopsies of different renal diseases were studied, analyzing by immunohistochemistry and in situ hybridization the possible expression of markers of proliferation (PCNA, Mib-1), cellular phenotype (vimentin, alpha-SMA, cytokeratin, ZO-1) and ECM production (prolyl 4-hydroxylase, HSP47, interstitial collagens). RESULTS: Independently of histological diagnosis, variable degrees of TEC positivity for PCNA (2.7 +/- 2.4 cells/field) and Mib-1 (1.9 +/- 2.3) were present. TECs expressing vimentin (1.4 +/- 4.7) and alpha-smooth muscle actin (alpha-SMA; 0.04 +/- 0.4) also were detected. It was possible to observe loss of epithelial antigens from 8 to 10% of the tubular cross sections. Moreover, TECs were stained by prolyl 4-hydroxylase (3.6 +/- 4.3), heat shock protein-47 (HSP47; 2.9 +/- 5.4), collagen type I (0.2 +/- 2.7) and type III (0.3 +/- 2.0). Collagen types I and III mRNAs were found in 0.8 to 1.4 cells/field. The number of TEC with EMT features were associated with serum creatinine and the degree of interstitial damage (P< or = 0.03), and even considering the 45 cases with mild interstitial lesions, the tubular expression of all markers remained strictly associated with renal function (P< or = 0.01). CONCLUSIONS: Our results suggest that, via transition to a mesenchymal phenotype, TEC can produce ECM proteins in human disease and directly intervene in the fibrotic processes. Moreover, the association of EMT features with serum creatinine supports the value of these markers in the assessment of disease severity.     

肥大细胞与间质性肾炎间质纤维化的关系

目的探讨急性间质性肾炎(AIN)、慢性间质性肾炎(CIN)肾间质中肥大细胞(MCs)浸润与间质纤维化之间的关系。方法随机选取患者肾穿刺组织作为研究样本。其中AIN组11例，CIN组16例，另选取微小病变病(MM)11例作为对照组，采用组织化学、免疫组织化学、免疫荧光双重染色方法观察MCs、蛋白酶活化受体-2(PAR-2)、转化生长因子-β1(TGF—β1)及Ⅰ型胶原(ColⅠ)在肾组织中的表达变化。结果(1)与MM对照组相比，AIN、CIN组肾间质。MCs数量明显增加。(2)MCs数量与肾小管上皮细胞PAR-2和TGF-β1表达面积及肾间质ColⅠ表达面积呈显著正相关；肾小管上皮细胞PAR-2与TGF-β1表达面积间也呈显著正相关。(3)MCs数量分别与肾间质PAR-2和TGF-β1阳性细胞数量呈显著正相关，MCs与肾间质PAR-2或TGF-β1染色阳性细胞存在部分重叠。结论。MCs可能参与AIN、CIN细胞外基质蓄积。其机制可能是通过活化．PAR-2．增加TGF-β1表达，促进ColⅠ合成。