福辛普利和氯沙坦对自发性高血压大鼠Toll样受体4表达的影响

Effects of fosinopril and losartan on expression of Toll like receptor 4 in spontaneously hypertensive rat

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： In order to study their therapy mechanism in the hypertensive renal damage, the impacts of fosinopfil and lorsartan on the expressions of TLR4, NF-κB, IL-6 and TNF-α in the spontaneously hypertensive rats （SHR） were investigated. Methodology：Twenty male SHRs with 22 weeks-old were randomly divided into four groups （ each of five rats） ： hypertensive group （ SHR）, Fosinopril treated group [10mg/（kg·d）], Lorsartan treated group [50mg/（kg·d）], and Fosinopril plus Lorsartan treated group [combination with Fosinopril 10mg/（kg·d） and Lorsartan 50mg/（kg·d）]. 5 male WKY rats with 22 weeks-old as the control group. After 8 weeks, the body weigh, cuff-tail blood pressure, 24 hours urinary protein excretion （Upro） , urinary N-acetyl-β-D-glucosaminidase （NAGase）, blood urea nitrogen （BUN） and serum creatinine （SCr） were measured. The pathological changes were viewed under light microscopy by HE. The mRNA expressions of TLR4, IL-6 and TNF-α were evaluated by Reverse transcription-polymerase chain reaction （RT-PCR）. The （nuclear） protein expressions of TLR4 and NF-KB were detected by Western Blot. The serum levels of IL-6 and TNF-α were tested by enzyme linked immunosorbentassay （ELISA）. Results：The typical pathological charac-teristics of hypertensive renal injury and infiltrative inflammatory cells were demonstrated in the kidney of SHR. After treat-ment with Fosinopril or/and Lorsartan for 8 weeks, the hypertensive renal injury was ameliorated, the blood pressure, Upro, urinary NAGase were also obviously lower than the SHR group （P〈0.05） , as well as the expressions of TLR4, IL-6, TNF-α and the neucleoprotein of NF-κB were significantly decreased （ P 〈 0.05 ）, but no cooperative effects were observed by these two drugs （ P 〉 0. 05 ）. Conclusion： Fosinopril and Lorsartan can decreased the levels of TLR4 and the correlated inflammatory factors, which maybe one of the therapy mechanisms in the hypertensive renal damage.