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Research on the Role of γ-GCS in the Interstitial Fibrosis of Lupus Nephritis

Author: ZhangBeiPing
Tutor: TaoZuo
School: Guangzhou Medical College
Course: Internal Medicine
Keywords: GCS Interstitial fibrosis Kidney tissue damage GSH Normal mice Tubular epithelial cells Oxidative damage Female mice Tubulointerstitial Inflammatory cells Factor Lupus nephritis The normal control group Lipid peroxides fibrosis Fibroblasts Mesangial cells Transcriptional level mRNA Glomerulosclerosis
CLC: R593.242
Type: Master's thesis
Year: 2010
Downloads: 27
Quote: 0
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Abstract


Background: Lupus nephritis is the most common complication of SLE, is also a common secondary glomerulonephritis, glomerular, vascular and interstitial renal damage is characterized by glomerular may develop late sclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis, the development of end-stage renal interstitial fibrosis, leading to kidney failure, kidney disease SLE affecting long-term prognosis is the most important factor; thus lupus Renal interstitial fibrosis pathogenesis is an important aspect of the treatment of SLE. Current studies suggest that TGF-β1 in renal interstitial fibrosis plays an important role in kidney tissue inflammation can stimulate excessive repair, tubular epithelial transdifferentiation promote glomerular mesangial cells and endothelial cell proliferation and ECM synthesis and accumulation, promote glomerulosclerosis and renal interstitial fibrosis. Studies have shown that TGF-β1 in patients with LN tubular epithelial cells and stromal fibroblasts was significantly elevated, is the process of renal interstitial fibrosis LN important stimulating factor. Its induced fibrosis by promoting ECM synthesis and inhibit its degradation to achieve. Plasminogen activator is a way to activate plasminogen into plasmin protease degradation maintaining matrix formation and fibrinolysis are in a dynamic equilibrium. Plasminogen activator inhibitor (Pal-l) in the blood most effective plasminogen activator physiological inhibitors, which combine with the activating agent to inhibit plasminogen activator. TGF-β1 can effectively stimulate the Pal-l expression in the kidney tissue, thereby inhibiting the degradation of ECM, contributing to its deposition in the renal interstitium large, this process is completed by the ROS-mediated. In the pathology of lupus nephritis, immune injury joint inflammation, leading to kidney tissue affected by various factors such as nitric oxide oxidation, such as the role of lipid peroxide formation damage, and eventually developed into the renal interstitial fibrosis in irreversible damage. Glutathione (GSH) is the body's antioxidant mechanism is one of the most important factors in the body can be effective against the damaging effects of oxidation factor. Latest News in vivo GSH levels in SLE patients was significantly lower than the normal control group, and is closely related with disease activity, thus affecting the renal tissue GSH levels in renal tissue damage to the development of renal interstitial fibrosis is an important factor; and also through the GSH and ROS inhibition of TGF-β-1 expression induced by Pal-l, prompting ECM degradation. Oxidative damage and other stimuli can be adjusted to varying degrees of renal tissue GSH concentration, one of the important aspects of the regulation is to regulate transcription of GSH synthesis rate-limiting enzyme-γ-glutamyl cysteine ??synthetase (γ-GCS), thereby regulating the intracellular GSH concentration, promote renal tissue injury repair or protect renal tissue from oxidative damage. To sum up, in LN patients reduced levels of GSH represents reduced antioxidant capacity, circulation of various oxidation factors directly on renal tissue damage, and mediated by TGF-β1-induced fibrosis. The LN renal tissue GSH level of transcription regulatory factors γ-GCS research, will be the LN mechanism of renal interstitial fibrosis, a new starting point. Objective: 1. Normal mice were observed in mice MRL/1pr mouse model of lupus renal fibrosis transcription factor TGF-β1 expression and protein levels change. 2 were observed in normal mice and GSH synthesis rate-limiting enzyme γ-GCS in mouse renal tissues MRL/1pr assess lupus hamster kidney tissue antioxidant capacity changes. Explore MRL/1pr mouse renal tissue GSH and γ-GCS expression changes in renal interstitial fibrosis. 3 Construct γ-GCS-pEGFP-c1 eukaryotic expression plasmid, cultured primary murine renal tubular epithelial cells. For subsequent studies γ-GCS expression in renal tubular epithelial cells to make early preparations. Method: 1. Grouping normal control group: 16-week-old SPF level C57BL / 6 female mice; LN model group: 16 weeks SPF level MRL/1pr female mice, each 10. 2 staining was observed in renal tissue pathology. 3 with quantitative PCR were detected in mouse renal tissue and fibrosis factor γ-GCS mRNA levels of TGF-β1 expression changed. 4 immunohistochemical detection of TGF-β1 protein changed. 5.westernbloting renal tissue was detected γ-GCS protein expression. Colorimetric detection of renal tissue GSH levels. 6 Using PCR and cloned γ-GCS sequence fragment cloned into pEGFP-c1 eukaryotic expression vector, enzymatic digestion and cultured primary renal tubular epithelial cells. 7 using SPSS 13.0 statistical software for analysis, data are expressed as mean ± standard deviation (x ± s) that compare two sample t-test. P lt; 0.05 was considered statistically significant. Results: 1. Pathological changes visible light microscope HE staining, lupus mice Groups section tubular epithelial cell atrophy, loss, lumen expansion, and tubular epithelial cells fibrosis, focal tubulointerstitial fibrosis, vacuolization and protein casts visible. (2) quantitative PCR results using semi-quantitative method of comparing γ-GCS and TGF-β1 in C57BL / 6 mice and MRL/1pr differential expression in murine renal tissue mRNA levels of γ-GCS group with normal mice compare decreased expression, TGF-β1 mRNA levels increased, the difference was statistically significant, (p are lt; 0.05). Lupus rat renal tissue GSH levels were significantly decreased (p lt; 0.05). 3 Immunohistochemical results showed that TGF-β1 in renal tubular epithelial cells mainly highly expressed. MRL/1pr renal tubular epithelial cells in mice than in normal mice (p lt; 0.05). Western blot results show that γ-GCS protein in murine renal tissue were decreased (p lt; 0.05). 4 successfully constructed γ-GCS-pEGFP-c1 eukaryotic expression vector and sequenced gene sequence with γ-GCSmRNA same sequence. Successfully cultured primary renal tubular epithelial cells. Early cells were mostly spindle or fusiform circle, hematoxylin staining nuclei light blue staining was observed for the larger multilateral cobblestone. Conclusion: LN renal tissue, inflammation of the high expression of TGF-β1 induced the expression of γ-GCS reduced, so that the GSH synthesis decreased, LN patients with renal tissue oxidation - antioxidant imbalance and kidney tissues of large quantities of ROS mediated fibrotic factor TGF-β1 in renal tissue fibrogenic effect, to some extent accelerated the process of renal interstitial fibrosis. The research for the future treatment of lupus nephritis study provides new guidance ideas for the pathogenesis of lupus nephritis laid the foundation for further research. Successfully constructed γ-GCS-pEGFP-c1 eukaryotic expression vector and successfully cultured primary renal tubular epithelial cells, for further study γ-GCS renal interstitial fibrosis in renal tubular epithelial cells in the role, made preparation.

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CLC: > Medicine, health > Internal Medicine > Systemic disease > Autoimmune diseases > Autoimmune diseases, connective tissue disease > Lupus erythematosus > Lupus nephritis
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