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The Effect of TNF-α on TEMT of Renal Interstitial Fibrosis and Inhibition Effect of Chinese Herbs Nourishing Kidney and Activing Blood on Transdifferentiation of Tubular Epithelium

Author: ZhangMianZhi
Tutor: DuanHuiJun
School: Hebei Medical University
Course: Pathology and Pathophysiology
Keywords: Renal interstitial fibrosis Aristolochic acid Tumor Necrosis Factor Tubular epithelial myofibroblast transdifferentiation BSHX method
CLC: R285
Type: PhD thesis
Year: 2004
Downloads: 288
Quote: 1
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Abstract


Objective: renal interstitial fibrosis (renal interstitial fibrosis, RIF) is a variety of end-stage renal disease common performance is closely related with chronic renal failure, the main pathological change is the reduction of the renal tubular epithelial cells, extracellular matrix accumulation, as well as certain stage interstitial myofibroblasts more (Myofibroblast, MyoF), the formation of myofibroblasts in renal interstitial fibrosis. Recent studies that the interstitial MyoF comes from the activation of fibroblasts, partly from tubule epithelial cell transdifferentiation. Tubular epithelial cells differentiate into myofibroblasts (tubular epithelial-myofibroblast trans-diffentiation, TEMT) may be one of the important mechanisms of progressive kidney disease interstitial fibrosis. Aristolochic acid (aristolochic acid, AA) Aristolochia main component of the plant, can directly damage renal tubular epithelial cells to transdifferentiation occurs, necrosis or apoptosis, resulting in renal interstitial fibrosis. A recent research report aristolochic acid-induced tubular epithelial cells myofibroblast transdifferentiation may be the main reason for renal interstitial fibrosis. Previous studies have found that transforming growth factor-β (Transforming growth factor-beta, TGF-beta), and b-fibroblast growth factor (b-fibroblast growth factor, bFGF) alone induced transdifferentiation of the cells of the small tube, but other cytokines The role is unclear, and TGF-β is the most powerful TEMT inducer, tumor necrosis factor-α (tumor necrosis factor-α, TNF-α) in renal tubular epithelial cell transdifferentiation yet to see the report. To explore the role of TNF-α in TEMT mechanism helpful for understanding of renal interstitial fibrosis. Western medicine such as adhesion molecules prevention RIF is still in the experimental stage, and has not been used clinically. Chinese anti-RIF research is still in its infancy, and only a small number of Chinese medicine and its extract more in-depth studies, little research of traditional Chinese medicine and the lack of in-depth system and the mechanisms. Tubular epithelial cells in vitro by using different concentrations of TNF-α stimulation, and the combined effects of TGF-β to observe the role of TNF-α transdifferentiation in renal tubular epithelial cells and renal interstitial fibrosis progress to explore whether TNF-α-induced human renal tubular epithelial cells (human kidney cell, HKC) cell phenotypic change occurs; addition by giving rats intraperitoneal injection of pure aristolochic acid-induced renal interstitial fibrosis, observed tubule cells transdifferentiation muscle into the role of fibroblasts in the fibrotic process, as well as the expression of TNF-α in the process of transdifferentiation; through unilateral ureteral ligation lt; WP = 5 gt; (Unilateral Ureteral Obstruction UUO) model, Application BSHX method traditional Chinese medicine treatment of renal interstitial fibrosis, and to explore the role of the traditional Chinese medicine prescriptions on the prevention and treatment of renal interstitial fibrosis. Method: First, select HKC cells for the study were divided into 4 groups: (1) negative control group; (2) TGF-β (8ng/ml) positive control group; various concentrations of TNF-α (3) (1 5,50,100 ng / ml); (4) TGF-β of TNF-α in combination group: TNF-alpha (50ng/ml), TGF-beta (8ng/ml) and TNF-α (100ng/ml) of TGF- β (8ng/ml). By morphological, indirect immunofluorescence, immunohistochemistry double staining technique and enzyme-linked immunosorbent assay to observe the groups HKC cells phenotypic changes and extracellular matrix formation. The second part of Wister rats were randomly divided into two groups, Group: A the the aristolochic acid experimental group (n = 30), given intraperitoneal injections of aristolochic acid, a dose of 5mg · kg-1 · d-1 administered a total of 16 weeks, 16 weeks after withdrawal observation, 6 rats were sacrificed at 8, 12, 16, 20, 24 weeks after treatment. Group B: normal control group (n = 6): given intraperitoneal injection of saline per 2 ml · d-1, a total of 16 weeks. Through blood, urine biochemical assays, observed by light microscopy and stereology measurements Immunohistochemical detection of total cellular RNA extraction and electrophoresis identification methods such as observation of aristolochic acid-induced tubular epithelial cells differentiate into myofibroblasts in renal role in the process of fibrosis and TNF-α in the process of transdifferentiation whether specific expression. Third part Wister rats 32 control group of eight, only sham surgery, and the remaining 24 in sterile conditions downstream unilateral ureteral ligation induced renal interstitial fibrosis model, were randomly divided into a treatment group and model group, the treatment group UUO surgery the first day to the traditional Chinese medicine, according to animal weight, high-dose and low dose gavage 4.0g · kg-1 · d-1 and 2.0g · kg-1 · d-1, respectively. each dose of eight animal model group of eight animals to the same amount of warm water. Tubular tissue by immunohistochemical detection of vimentin (vimentin, Vim), keratin (cytoketatin, CK)? - Smooth muscle actin (α-smooth muscle actin, α-SMA) expression, and quantitative analysis of tubular epithelial intracellular immunohistochemical ratio of the positive area and the total area of ??the tubular epithelial cells, the mean value of the comparative value of specimens of renal tubular epithelial cells positive expression. RESULTS: The first part, TNF-α (50,100 ng / ml) induced the HKC cells lose expression cadherin and keratin expression of α-SMA and vimentin, fibronectin and type I collagen concentration in the cell culture supernatant increased; combined effects of TNF-α (50, 100 ng / ml), and TGF-β (8ng/ml) HKC cells express α-SMA, cell culture supernatant fibronectin and type I collagen were significantly higher than alone group (P lt; 0.05); TNF-α (50ng/ml), and TGF-β (8ng/ml) starting from 24 hours significantly increased the concentration of the fibronectin and type I collagen, 72 hours LT; WP = 6 gt; continue to rise, (P lt; 0.05). The second part, in aristolochic acid renal interstitial fibrosis in animal models, blood BUN and Scr 16 weeks after treatment compared with the control group was significantly higher (P lt; 0.05), stop the medication after blood BUN stagnation but continues to rise; specimens visible renal smooth surface, no uneven aristolochic acid in renal cortical thinning in the 16 weeks after kidney weight compared with control group decreased, especially after 16-24 weeks decreased significantly (P lt; 0.01); visible the aristolochic acid group after 16 weeks (-SMA and vimentin immunohistochemistry in renal tubular epithelial cells, a small amount of expression was significantly increased at 20 weeks, 24 weeks when the expression was further enhanced; After 16 weeks of keratin expression began to weaken, but in 20, 24 weeks to further reduce the significant difference (P lt; 0.01), compared with the control group; control group without TNF-α of TGF-?

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