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Role of TGF-β1/Smad Signal Transduction Pathway in Experimental Diabetic Nephropathy

Author: HeNing
Tutor: DuanHuiJun
School: Hebei Medical University
Course: Pathology and Pathophysiology
Keywords: Diabetic nephropathy Smad protein transforming growth factor-β signal transduction extracellular matrix glomerulosclerosis tubulointerstitial fibrosis
CLC: R587.2
Type: Master's thesis
Year: 2004
Downloads: 234
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Abstract


Objective: Diabetic nephropathy (DN) is one of the common and serious diabetic complications. Almost 1/3 of cases with end stage renal failure are caused by DN. Transforming growth factor-β(TGF-β) is the main intermedium between renal damage and some biological factors including cytokines. TGF-βcould directly cause the characteristic pathologic changes of DN, including renal cell hypertrophy, extracellular matrix excessive accumulation, glomerulosclerosis, tubulointerstitial fibrosis, and so on.The cytokines of TGF-βfamily has many biological effects through different signal transduction pathways, among which, Smad protein family play an important role. The process of transmembrane signaling depended on the Smad protein family, which regulate kinds of gene expression. In the present study, We investigate the expression of TGF-β1 and its signal transduction elements (Smad2/3, Smad7), and renal extracellular matrix accumulation in the renal tissues of experimental diabetes, to further clarify the effects of Smads on the development of DN.Methods: Experimental diabetes were induced in uninephrectomized Wistar rats by intraperitoneal injection of <WP=8>STZ (streptozotocin). The animals were divided into two groups: group A (control) and group B (diabetes mellitus). The rats of group B received a single intraperitoneal injection of STZ dissolved in 0.1mol/L sodium citrate (pH 4.5) at a dose of 65mg/kgWT. The rats of group A only received an injection of the same volume of 0.1mol/L sodium citrate. The model of diabetes mellitus was considered to be successful when the blood glucose was ≥16.7mmol/L and the urine glucose was +++~++++ after 48~72 hours of the injection. The rats of both groups were respectively sacrificed in the same number (n=6) at week 8, week 16 and week 24 after injection. The residual kidneys were removed and prepared for light microscopy, immunohistochemistry, flow cytometry, western blot and in situ hybridyzation. The protein expression of Smad2/3, Smad7, TGF-β1,collagen IV, Laminin was evaluated by immunohistochemistry. Smad2/3, Smad7 proteins were quantitatively analysed further by flow cytometry. In situ hybridyzation was used to detect the mRNA expression of Smad2/3 and TGF-β1. All the data were expressed as the form of . T test and F test were used to analyse the difference between the two groups and within one group. Statistical analysis was finished with SPSS software.Results: 1. Compared with group A of the corresponding period, the blood glucose, BUN and Urine protein of group B were higher. 2. The glomerular enlargement mesangial expansion and vacuole in some tubular cells were observed in diabetic rats. <WP=9>At week 24, the morphologic changes were more obvious, including tubular atrophy, hyaline casts in tubular lumen, basement membrane thickening, interstitial expension and fibrous tissue proliferation. 3. Immunohistochemically, the positive expression of TGF-β1 was observed in glomerular epithelial cells and mesangial area, capillary loops, epithelial cells of Bowman’s capsule and renal tubular cytoplasm. The expression of group B was significantly increased in contrast to group A. The positive expression of Smad2/3 was mainly seen in renal tubular cytoplasm, rarely in mesangial area. It was significantly increased in group B in contrast to group A. From week 8 to week 24, the positive expression of group B increased gradually. Positive staining for Smad7 was observed in renal tubular cytoplasm of group A. In group B it increased gradually from week 8 to week 16, then decreased at week 24. The positive expression of collagen Ⅳ and Laminin was observed in mesangial area, capillary basement membrane and tubular interstitial. In group B at week 24 it was markedly increased. 4. Flow cytometry showed that the expression of Smad2/3 protein in the kidneys of diabetic rats increased significantly at weeks 8, 16 and 24. Smad7 protein increased significantly in the kidneys of diabetic rats at week 8, reaching peak value at week 16, afterward it decreased at week 24. 5. T

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CLC: > Medicine, health > Internal Medicine > Endocrine diseases and metabolic diseases > Islet disease > Diabetic coma and other complications
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