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目的:研究福辛普利(fosinopril)和氯沙坦(losartan)干预自发性高血压大鼠(SHR)后Toll样受体4(TLR-4)、NF-κB、IL-6、TNF-α等基因的表达,探讨其在治疗高血压肾损伤中的作用机制。方法:20只22周龄雄性SHR,随机分为4组(5只/组):高血压组(SHR模型组),Fosinopril组[10mg/(kg.d)],Losartan组[50mg/(kg·d)],联合治疗组[fosinopril 10mg/(kg·d)+losartan50mg/(kg·d)];另22周龄雄性WKY大鼠5只为正常对照,共喂养8周。检测各组大鼠体重、尾动脉收缩压、24h尿蛋白定量(Upro)、尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG酶)、血尿素氮(BUN)及血肌酐(SCr)等。HE染色观察大鼠肾脏病理改变,RT-PCR检测TLR-4、IL-6、TNF-αmRNA表达;WesternBlot检测TLR-4蛋白及NF-κB核蛋白表达;ELISA检测血清IL-6及TNF-α水平。结果:SHR肾脏出现高血压肾损伤的病理特征,并伴有小管间质的炎性细胞浸润。Fosinopril、Losartan干预8周后,肾脏病理改变减轻,SHR收缩压、Upro及尿NAG酶均明显降低(P<0.05)。TLR-4 mRNA及蛋白表达均明显下调(P<0.05)。NF-κB核蛋白表达显著受抑制(P<0.05)。血清IL-6及TNF-α水平显著下降(与模型组比较均P<0.05)。联合治疗组较单药组无明显协同作用(P>0.05)。结论:Fosinopril和Losartan可下调TLR-4基因及相关炎症介质的表达,可能是其治疗高血压肾损伤的作用机制之一。
Objective: To investigate the effects of fosinopril and losartan on the expressions of TLR-4, NF-κB, IL-6 and TNF-α in spontaneously hypertensive rats (SHR) And other genes expression, explore its mechanism in the treatment of hypertensive renal injury. Methods: Twenty male SHRs of 22 weeks old were randomly divided into 4 groups (5 rats / group): hypertension group (SHR model group), Fosinopril group (10 mg / (kg · d) · D)], combined treatment group [fosinopril 10mg / (kg · d) + losartan50mg / (kg · d)]; the other 22 weeks old male WKY rats 5 as a normal control, feeding for 8 weeks. The body weight, systolic pressure of the tail artery, Upro, urine NAG, BUN and SCr were measured in each group. Wait. The expression of TLR-4, IL-6 and TNF-αmRNA was detected by RT-PCR. The expression of TLR-4 protein and NF-κB nuclear protein were detected by Western Blot. The levels of IL-6 and TNF- Level. Results: The renal pathology of SHR kidney appeared hypertensive renal injury accompanied by inflammatory cell infiltration of tubulointerstitium. After 8 weeks of Fosinopril and Losartan intervention, pathological changes of kidney were alleviated, SHR systolic pressure, Upro and urine NAG enzyme were significantly decreased (P <0.05). TLR-4 mRNA and protein expression were significantly decreased (P <0.05). NF-κB nuclear protein expression was significantly inhibited (P <0.05). Serum IL-6 and TNF-α levels decreased significantly (P <0.05 compared with the model group). Combination therapy group than the single drug group no significant synergies (P> 0.05). Conclusion: Fosinopril and Losartan can down-regulate the expression of TLR-4 gene and related inflammatory mediators, which may be one of the mechanisms of its treatment for hypertensive renal injury.