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目的探讨阿托伐他汀不依赖降血脂的肾脏保护作用的可能机制。方法雄性C57BL小鼠给予普通饮食作为对照组,CD36/SR-A/ApoE三敲小鼠随机分为高脂组和治疗组(高脂+阿托伐他汀)。实验满14周后处死取标本。采用酶法检测血清脂质水平;油红“O”染色检测肾组织内脂质沉积情况,H-E、PAS、Masson染色观察肾脏形态学改变;定量PCR技术与免疫组化检测肾组织转化生长因子(TGF-β)、纤维连接蛋白(fibronectin)、Ⅰ型胶原、Ⅳ型胶原、α肌动蛋白(α-SMA)表达。结果阿托伐他汀能够减少三敲小鼠肾脏组织脂质沉积,但血清中的脂质水平无明显降低。阿托伐他汀可以减少高脂饮食诱导的肾脏组织系膜细胞的增生、系膜基质的沉积,肾小管间质炎症细胞的浸润、肾小管的变性扩张,细胞外基质的沉积。阿托伐他汀不但可以明显降低肾脏组织TGF-β的基因与蛋白表达,还降低纤维化相关因子的基因与蛋白表达。结论阿托伐他汀可不依赖降血脂,独立于SR-A、CD36受体途径而发挥肾脏保护作用;这种作用可能是通过降低TGF-β的表达而实现的。
Objective To investigate the possible mechanism of atorvastatin independent of lipid-lowering renal protection. Methods Male C57BL mice were given normal diet as control group. CD36 / SR-A / ApoE triple knock mice were randomly divided into hyperlipidemia group and treatment group (high fat + atorvastatin). After 14 weeks of experiment, the specimens were sacrificed. Serum lipid levels were detected by enzyme-linked immunosorbent assay (ELISA). Lipid deposition in renal tissues was detected by oil red staining and immunohistochemical staining with HE, PAS and Masson staining. Quantitative PCR and immunohistochemistry (TGF-β), fibronectin, collagen type Ⅰ, type Ⅳ collagen and α-actin (α-SMA). Results Atorvastatin decreased lipid deposition in kidney tissue of triple knock-in mice, but no significant decrease in serum lipid levels. Atorvastatin can reduce hyperplasia of renal mesangial cells induced by high-fat diet, deposition of mesangial matrix, infiltration of tubulointerstitial inflammatory cells, degeneration and expansion of renal tubules and deposition of extracellular matrix. Atorvastatin not only can significantly reduce the TGF-β gene and protein expression in the kidney, but also reduce the expression of fibrosis-related genes and proteins. Conclusions Atorvastatin may play a protective role independent of the effects of hypolipidemic agents on the SR-A and CD36 receptors. This effect may be attributed to the decrease of TGF-β expression.