丁酸通过激活G蛋白偶联受体41/43通路降低高血压大鼠血压

Butyrate reduces blood pressure in hypertensive rats by activating the G protein-coupled receptor 41/43 pathway

目的探讨丁酸通过激活G蛋白偶联受体41/43(GPR41/43)通路降低高血压模型大鼠血压的机制。方法75只雄性SD大鼠随机分为假手术组(15只)和造模组(60只),采用两肾一夹方法建立高血压大鼠模型,将成模鼠随机分为对照组(超纯水0.1 mL/kg)、丁酸高剂量组(220 mg/kg)、丁酸低剂量组(110 mg/kg)和缬沙坦组(30 mg/kg),每组15只,连续灌胃给药4周。分别在给药前后测量大鼠尾动脉收缩压(SBP)及心率(HR)。采用酶联免疫吸附试验(ELISA)检测大鼠血清中白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)及内皮型一氧化氮合酶(eNOS)含量;实时荧光定量PCR(qPCR)检测大鼠胸主动脉组织中IL-6、TNF-α、eNOS的mRNA表达水平。免疫组织化学染色检测大鼠胸主动脉GPR41/43表达量。结果给药2周,对照组大鼠SBP较假手术组显著升高(P<0.05),丁酸高剂量组、丁酸低剂量组、缬沙坦组SBP较对照组降低,且丁酸高剂量组低于低剂量组(P<0.05)。给药4周,丁酸高剂量组较丁酸低剂量组SBP明显降低(P<0.05);给药前后各组大鼠HR差异均无统计学意义(P>0.05)。给药后丁酸高剂量组、丁酸低剂量组eNOS蛋白和mRNA表达量较对照组增加,IL-6、TNF-α蛋白及mRNA表达量均降低(P<0.05)。免疫组织化学染色显示,大鼠胸主动脉组织的GPR41/43表达较对照组增加,且高于缬沙坦组(P<0.05)。结论丁酸对高血压大鼠有明显的降压作用,可能与激活GPR41/43通路增加血管舒张,抑制炎性因子表达有关。

Objective To investigate the mechanism of butyrate reducing blood pressure in hypertensive model rats by activating G protein-coupled receptor 41/43(GPR41/43)pathway.Methods Seventy-five male SD rats were randomly divided into the sham operation group(n=15)and the model group(n=60).Hypertensive rat model was established by two kidneys and one clip method.Model rats were randomly divided into the control group(0.1 mL/kg ultra-pure water),the butyrate high-dose group(220 mg/kg),the butyrate low-dose group(110 mg/kg)and the valsartan group(30 mg/kg),with 15 rats in each group.Rats were given intervention by cntinuous gavage for 4 weeks.Caudal artery systolic blood pressure(SBP)and heart rate(HR)were measured before and after administration.The serum levels of interleukin-6(IL-6),tumor necrosis factor-α(TNF-α)and endothelial nitric oxide synthase(eNOS)were detected by enzyme-linked immunosorbent assay(ELISA).The mRNA expression levels of IL-6,TNF-αand eNOS in thoracic aorta were detected by real-time fluorescent quantitative PCR(qPCR).The expression of GPR41/43 in rat thoracic aorta was detected by immunohistochemistry.Results After 2 weeks of administration,SBP was significantly higher in the control group than that in the sham operation group(P<0.05).Values of SBP were significantly lower in the high dose butyrate group,the low dose butyrate group and the valsartan group than those in the control group,and SBP was significantly lower in the butyrate high dose group than that of the butyrate low dose group(P<0.05).After 4 weeks of administration,SBP was significantly lower in the high dose group than that in the low dose group(P<0.05).There were no significant differences in HR before and after administration between groups(P>0.05).After administration,the protein expression and mRNA expression of eNOS were increased in the butyrate high dose group and the butyrate low dose group compared with those of the control group,and the protein expression and mRNA expression of IL-6 and TNF-αwere decreased(P<0.05).Immunohistochemistry showed that the expression of GPR41/43 in rat thoracic aorta tissue was increased compared with that of the control group,and which was higher than that in the valsartan group(P<0.05).Conclusion Butyrate has a significant antihypertensive effect on hypertensive rats,which may be related to the activation of GPR41/43 pathway to increase vasodilation and inhibit expression of inflammatory factors..