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目的:研究P38信号通路(P38MAPK)与Ⅳ型胶原(ColⅣ)蛋白及纤维连接素(FN)mRNA表达的关系,探讨P38MAPK在糖尿病肾病中的作用,以及辛伐他汀(SI)在防治糖尿病肾病中的作用机制。方法:在体外模拟糖尿病状态,分别以高葡萄糖(HG)、糖基化终末产物(AGE)或过氧化氢(H2O2)孵育大鼠肾小球系膜细胞(RMC),以Westernblot或RT-PCR检测P38MAPK和ColⅣ及FN在RMC中蛋白或mRNA的表达。检测并比较有无P38MAPK特异性抑制剂(SB203580)或SI预处理时,以上3种因素对P38MAPK和ColⅣ蛋白及FNmRNA在RMC中表达的影响。结果:HG、AGE或H2O2均可单独激活P38MAPK,增强磷酸化P38MAPK、ColⅣ及FN在RMC中的表达。SB203580可显著抑制ColⅣ蛋白及FNmRNA的表达;SI可抑制P38MAPK的活化并减少ColⅣ蛋白及FNmRNA的表达。结论:P38MAPK是ColⅣ及FN的上游信号分子,表明P38MAPK可能是糖尿病肾病发生的始动信号之一。SI可能是通过抑制P38MAPK磷酸化进而抑制ColⅣ蛋白及FNmRNA的表达,具有防治糖尿病肾病的作用。
Objective: To investigate the relationship between P38 MAPK and Col Ⅳ protein and fibronectin (FN) mRNA expression in diabetic nephropathy and the role of simvastatin (SI) in the prevention and treatment of diabetic nephropathy The mechanism of action. Methods: The diabetic rat models were induced by high glucose (HG), advanced glycation end products (AGE) or hydrogen peroxide (H 2 O 2), respectively. The rat mesangial cells (RMCs) PCR was used to detect the protein or mRNA expression of P38MAPK, ColⅣ and FN in RMC. The effects of above three factors on the expression of P38MAPK, ColⅣ protein and FN mRNA in RMC were detected and compared with or without P38MAPK specific inhibitor (SB203580) or SI pretreatment. Results: HG, AGE or H2O2 could activate P38MAPK alone and enhance the expression of phosphorylated P38MAPK, ColⅣ and FN in RMC. SB203580 could significantly inhibit the expression of ColⅣ protein and FN mRNA; SI could inhibit the activation of P38MAPK and decrease the expression of ColⅣ protein and FN mRNA. Conclusion: P38MAPK is an upstream signaling molecule of ColⅣ and FN, indicating that P38MAPK may be one of the initiating signals of diabetic nephropathy. SI may be through the inhibition of P38MAPK phosphorylation and thus inhibit Col Ⅳ protein and FN mRNA expression, with the prevention and treatment of diabetic nephropathy.