前蛋白转化酶枯草溶菌素9在肾病综合征高血脂症中的作用及洛伐他汀干预对其的影响

Role of proprotein convertase subtilisin/kexin type 9 in hyperlipemia of nephrotic syndrome and the effects of lovastatin intervention

目的构建阿霉素肾病综合征大鼠模型,探讨前蛋白转化酶枯草溶菌素9(PCSK9)在肾病综合征高血脂症中的作用,以及应用他汀类药物干预对它的影响。方法将雄性SD大鼠随机分成3组:正常对照组、肾病综合征对照组、肾病综合征治疗组(n=6)。大鼠一次性尾静脉注射阿霉素7mg/kg构建肾病综合征模型,正常对照组给予等量生理盐水尾静脉注射。造模2周后,肾病综合征治疗组使用洛伐他汀20mg/kg灌胃2周,肾病综合征对照组及正常对照组等量羧甲基纤维素钠(CMC)灌胃治疗。荧光定量聚合酶链反应(PCR)法检测各组大鼠肝组织低密度脂蛋白受体(LDLR)及PCSK9的mRNA表达;Western blot法检测各组肝组织PCSK9蛋白表达,同时检测大鼠相关血生化指标。结果肾病综合征对照组大鼠血清白蛋白低于正常对照组,肾病综合征治疗组的白蛋白与肾病综合征对照组的差异无统计学意义。3组大鼠的血肌酐差异无统计学意义。正常对照组与肾病综合征治疗组的血清胆固醇、LDL-C水平低于肾病综合征对照组[(1.18±0.14)、(3.29±1.84)比(8.39±5.57)mmol/L;(0.30±0.25)、(0.63±0.54)比(1.34±0.70)mmol/L;均P<0.05],但肾病综合征治疗组和正常对照组间差异无统计学意义。3组之间LDLR mRNA表达量差异无统计学意义;肾病综合征对照组、肾病综合征治疗组PCSK9的mRNA及蛋白表达量均高于正常对照组;同时肾病综合征治疗组PCSK9的mRNA及蛋白表达量也高于肾病综合征对照组,差异均有统计学意义。结论肾病综合征高血脂症中PCSK9表达上调,同时他汀药物治疗可以进一步上调其表达。

Objective To explore the role of proprotein convertase subtilisin/kexin type 9（PCSK9）in hyperlipemia of nephrotic syndrome and the effects of lovastatin intervention. Methods Eighteen male SD rats were randomly divided into three groups：control group,nephropathic group and statin treatment group（n=6）. Nephrotic rat models were established by single injection of adriamycin（7 mg/kg）via tail vein,while the control group was given saline injection by the same dosage. After two weeks,lovastatin treatment group was given by intragastric administration with lovastatin（20 mg/kg,×2 weeks）. The expression of low-density lipoprotein receptor（LDLR）and PCSK9 in rat liver tissues were detected by quantitative polymerase chain reaction（Q-PCR）and Western-blot analysis,and blood biochemical indexes were measured. Results Serum albumin in nephrotic syndrome group was lower than in control group,and there was no significant difference between control group and statin treatment groups.Levels of serum creatinine and triglycerid（TG）had no statistical difference among three groups.The levels of serum total cholesterol and low density lipoprotein cholesterol（LDL-C）in control group and lovastatin treatment group were significantly lower than in nephrotic syndrome group[（1.18±0.14）,（3.29±1.84）vs（8.39±5.57）mmol/L;（0.30±0.25）,（0.63±0.54）vs（1.34±0.70）mmol/L;all P〈0.05]. The expression of LDLR mRNA had no statistical difference among three groups. Compared with normal control group,the other two groups presented a significant elevation of mRNA and protein expression of PCSK9 in liver. Additionally,there was a marked up-regulation of PCSK9 in lovastatin treatment group compared with nephrotic syndrome group. Conclusion Hyperlipidemia in nephrotic syndrome is associated with up-regulation of PCSK9,and statin treatment can further increase the expression of PCSK9.