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Effects of Low Protein Diet Supplemented with α-ketoacid on Renal Interstitial Fibrosis and EMT in Adenine-induced Chronic Renal Failure Rats

Author: LiuYanPing
Tutor: ZhengFaLei
School: Peking Union Medical College , China
Course: Nephrology
Keywords: Adenine-induced rat model of chronic renal failure Low-protein diet Low-protein alpha - keto acid diet Renal interstitial fibrosis Tubular epithelial cell transdifferentiation α- smooth muscle actin E - cadherin Transforming growth factor-β1 Monocyte chemoattractant protein-1 Vascular endothelial growth factor Thrombospondin -1
CLC: R692.5
Type: Master's thesis
Year: 2007
Downloads: 134
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Abstract


Background and Purpose Previous studies have shown that low-protein diet (Low Protein Diet, LPD) and LPD α-keto acid (α-ketoacid, α-KA) has the role of delaying chronic renal failure (Chronic RenalFailure, CRY) progress. Renal interstitial fibrosis is closely related to the deterioration of renal function, is the main pathological features of progressive kidney disease. Tubular epithelial - mesenchymal cell transformation (epithelia-mesenchymal transition, EMT) is one of the important mechanisms of tubulointerstitial fibrosis progression. Studies have shown that transforming growth factor-β1 (TGF-β1), monocyte chemoattractant protein -1 (MCP-1) the formation of interstitial fibrosis in participation, can be induced tubular epithelial cell EMT; vascular endothelial cell growth decreased expression of the factor (VEGF), angiogenesis inhibitors (TSP-1) expression is closely related with the degree of renal interstitial fibrosis. LPD α-KA kidney protective mechanism of inhibition of renal tubular epithelial cell transdifferentiation related has not been reported. The main purpose of this study is to observe the LPD and LPD α-KA adenine-induced CRF rat model of renal interstitial fibrosis, and transdifferentiation of renal tubular epithelial cells, and to explore its mechanism. 46 male Wistar rats were divided into normal control group (n = 10), the CRF model group (n = 36). CRF model group gavage 5% adenine solution (150mg/kg/d), for six weeks, and then were randomly divided into the NPD group (22% protein content diet, n = 12), the LPD group (6% of the protein content of feed feeding, n =) and LPD α-KA group (5% protein 1% EAA-α-KA preparations diet), the animals were observed growth, respectively, in the first 10 weeks, the animals were killed over the weekend of the 14th, put to death the day before sacrificing 24 hour urine specimens were killed after sacrificing blood and kidney tissue. The application automatic analyzer serum creatinine, blood urea nitrogen, calcium, phosphorus, hemoglobin, and 24-hour urine protein, urine creatinine indicators; Masson staining analysis of the degree of renal interstitial fibrosis; α smooth muscle actin in renal tissues was measured by immunohistochemical methods protein (α-SMA), E-cadherin (E-cadherin), TGF-β1, MCP-1, VEGF and TSP-1-positive cells in the area, the application of double-blind method CMIAS multifunction true color pathological image analysis system on the immune group to analyze the results; renal cortex was measured by RT-PCR and Western blot method of α-SMA, TGF-β1, MCP-1, VEGF and TSP-1 mRNA or protein expression levels, UVI gel imaging analysis system scan and recording the intensity of the optical density, the expression intensity of the target band represented by the ratio of the optical density and the GAPDH or β-actin optical density. Results 1. Renal function: CRF group of animal serum creatinine, blood urea nitrogen level increased to 10 weeks, LPD, LPD of α-KA group blood BUN significantly lower than the NPD group (P <0.01), but no difference between the two groups; 14 weeks NPD LPD and LPD α-KA group was not significantly different; different time points, CRF groups serum creatinine was not significantly different; 2. Anemia: different time points in each group, CRY hemoglobin decreased, and no significant difference among the three groups; 3. Proteinuria: a different point in time, NPD group, 24-hour urinary protein excretion increased significantly LPD group, LPD α-KA group a significant reduction in 24-hour urinary protein excretion, no significant difference in the two groups; 4. Serum levels of calcium and phosphorus: a different point in time, the NPD group showed lower serum calcium, elevated serum phosphorus, the 14 weeks LPD and LPD α-KA serum calcium were significantly higher than the NPD group (P <0.001) between the two groups was not significantly different ; LPD and LPD α-KA serum phosphorus level with the NPD group no significant difference; 5. MASSON staining results: different time points, CRY among groups qualitative fibrosis extent of gradually heavier, and the LPD, LPD α-KA group significantly with lighter than NPD group, at 10 weeks, the difference between the LPD and LPD α-KA is not significant with 14 weeks when, LPD α-KA group of renal interstitial fibrosis lightest among the three groups (LPD α-KA vs LPD, P <0.05); The EMT testing situation: kidney tissue immunohistochemistry results showed that the LPD and LPD α-KA 10 weeks of α-SMA expression in renal tissue reduction than the NPD group, there is no difference between the two, the 14 weeks of this effect is not obvious ; Correspondingly, at 10 weeks, 14 weeks of observation, LPD, LPD α-KA Group E-cadherin expression than the NPD group significantly enhanced LPD α-KA this role more significant (LPD α -KA vs LPD, P <0.05). Western Blot method show that the the LPD treatment group and LPD α-KA group protein expression of α-SMA below the NPD group. 7. VEGF and TSP-1 expression: CRY rat model of VEGF tissue protein levels down (immunohistochemistry and Western blot confirmed); lesion 10 weeks, TSP-1 expression was significantly up-regulated (immunohistochemistry, RT-PCR confirmed ), there is no difference between the expression of TSP-1mRNA 14 weeks with control. Different time points, LPD α-KA group VEGF expression levels were significantly increased than the NPD group (immunohistochemistry confirmed by RT-PCR and Westernblot method). The LPD α-KA regulation of VEGF expression was significantly superior to the LPD. LPD Q-KA group at 10 weeks TSP-1 expression was significantly weakened (immunohistochemistry, RT-PCR), TSP-1 expression in each group was not significantly different in the 14 weeks. 8. TGFβ1 and MCP-1 expression changes: different time points, compared with the normal control group, the NPD group, group LPD and LPD αKA group of kidney tissue TGFβ1 group of staining positive area percentage were significantly increased, at 10 weeks, LPD αKA group significantly with low CRF NPD group, 14 weeks were no significant differences among the groups TGFβ1. Different time points, compared with the normal control group, NPD Group, the LPD group and LPD αKA of renal tissue MCP-1 immune staining percentage of positive stained area and mRNA expression levels were increased, but no significant difference between the groups. Conclusion This experimental conditions: 1. LPD α-KA and LPD have to reduce the role of adenine-induced CRF rats proteinuria. 2. LPD α-KA and LPD alleviating the adenine-induced the CRF rat renal interstitial fibrosis LPD α-KA stronger. 3. LPD α-KA and LPD were rat kidney tissue EMT role, the role may be related to reduced renal interstitial fibrosis-related. 4. LPD α-KA TGFβ1 overexpression part of the inhibition of MCP-1 expression, but not observed, the exact role needs further study. 5. LPD α-KA and LPD can be raised renal VEGF expression, inhibition of TSP-1 expression, LPD α-KA role more significant. LPD α-KA, LPD adjust the experimental animal kidney tissue VEGF and TSP-1 expression may be related to the inhibition of EMT occurrence, the exact mechanism needs further research.

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CLC: > Medicine, health > Surgery > Urology ( urinary and reproductive system diseases) > Kidney disease > Renal failure
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