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目的考察醛糖还原酶抑制剂拉辛司克(laxinskat)治疗糖尿病肾病的作用及分子作用机制。方法采用KKAy小鼠给予高脂饲料制造小鼠糖尿病肾病模型,通过测定血清C反应蛋白CRP(c-reaction protein)含量和肾皮质醛糖还原酶AR(aldose reductase)活性考察拉辛司克对糖尿病肾病的保护作用及作用部位。采用体外高糖条件下培养大鼠肾小球系膜细胞制备糖尿病肾病细胞模型,采用MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)法考察拉辛司克抑制肾小球系膜细胞增生作用,并利用Western-Blot技术测定细胞内P21蛋白质含量,确定其分子机制。结果整体水平上拉辛司克,23 mg·kg~(-1)剂量能够明显减少糖尿病肾病模型小鼠CRP含量,降低肾皮质内AR含量,作用与依帕司他相当;细胞水平上拉辛司克,10、100μmol·L~(-1)能够增加肾小球系膜细胞肾小球系膜细胞内P21蛋白生成,抑制细胞生长,改善细胞增生肥大,作用强与依帕司他(epalrestat,EPAL)。结论拉辛司克(laxinskat)能够改善KKay糖尿病肾病模型小鼠肾病发展进程,其作用部位可能在肾脏皮质部;通过细胞模型研究确定其治疗糖尿病肾病的机制与促进肾小球系膜细胞P21蛋白生成从而抑制细胞生长有关,作用机制与依帕司他不完全相同。
Objective To investigate the effect and molecular mechanism of aldose reductase inhibitor laxinskat on diabetic nephropathy. Methods The mouse model of diabetic nephropathy was induced by high-fat diet with KKAy mice. The effects of Rasirinik on diabetes mellitus (T2DM) were evaluated by measuring the content of c-reactive protein (CRP) and aldose reductase (AR) Nephropathy protection and role of the site. The rat glomerular mesangial cells were cultured under high glucose conditions in vitro to prepare diabetic nephropathy model. The effects of Racinc G inhibition of mesangial cell proliferation, and the use of Western-Blot determination of intracellular P21 protein content, to determine the molecular mechanism. Results At the overall level of RAS, the dose of 23 mg · kg ~ (-1) could obviously reduce the content of CRP in diabetic nephropathy model mice and decrease AR content in renal cortex, which was comparable to that of epalrestat; Shike 10,100μmol·L -1 could increase the production of P21 protein in glomerular mesangial cells, inhibit the cell growth and improve the cell proliferation and hypertrophy, and the effect was stronger than that of epalrestat , EPAL). Conclusion Laxinskat can improve the progression of nephropathy in KKay diabetic nephropathy model mice, and its role may be in the cortex of the kidney. To determine its mechanism of treating diabetic nephropathy and promote the expression of P21 protein in mesangial cells Generated to inhibit cell growth, the mechanism of action and epalrestat is not exactly the same.