肾上腺髓质素对自发性高血压大鼠肾脏微小动脉的影响

Effect of adrenomedullin on renal arteriole remodeling in spontaneous hypertensive rats

目的探讨肾上腺髓质素(Adrenomedullin,ADM)对自发性高血压大鼠(SHR)肾脏微小动脉的影响及与磷酸化细胞外调节蛋白激酶1/2(ERK1/2)的关系。方法 4周龄雄性SHR随机分为ADM治疗组(ADM组)和高血压对照组(SHR组),以WKY大鼠作为空白对照,ADM组皮下注射ADM(1.0 nmol/kg·d,每周5 d)。采用组织学、组织化学、免疫组织化学和Western blot技术,对比观察平均动脉收缩压、肾微小动脉组织学变化和磷酸化ERK1/2表达。结果从8周龄开始,SHR和ADM组血压开始升高,16和24周龄平均动脉收缩压明显高于WKY组,ADM治疗组24周龄时平均动脉收缩压明显低于非治疗SHR组;在16和24周龄,SHR组和ADM组大鼠肾脏微小动脉中膜/内径比值明显大于WKY组(P<0.05);ADM组大鼠肾脏微小动脉中膜/内径比值的增幅略低于SHR组,其中外径小于40μm动脉中膜/内径比值在24周龄时明显小于SHR组(P<0.05)。免疫组织化学和Western blot显示16和24周龄SHR和ADM组大鼠肾脏组织磷酸化ERK1/2表达显著高于WKY组(P<0.05),24周龄时ADM组肾脏磷酸化ERK1/2表达显著低于SHR组(P<0.05)。结论较长时间使用ADM,在一定程度上能够减轻自发性高血压大鼠血压升高程度,可能通过抑制ERK1/2的磷酸化减轻肾微小动脉的重构。

Objective To investigate the effect of adrenomeduUin （ADM） on renal arteriole remodeling and phosphorylation of extracellular signal-regulated protein kinases 1/2 （p-ERK1/2） in spontaneous hypertensive rats （SHR）. Methods Male SHR （4 weeks old） were randomized into hypertensive group （SHR） and ADM-treated group （ADM） to receive subcutaneous saline and ADM injections （daily dose of 1.0 nmol/kg, 5 days a week）, respectively, with age-matched Wistar-Kyota （WKY） rats as the blank control. The systolic blood pressure （SBP） was measured at the end of each week, and histological changes of the renal arterioles were observed using HE and Weigert staining; the expression of P-ERK1/2 in the arterioles was detected with immunohistochemistry and Western blotting. Results At 16 and 24 weeks of age, the rats in both SHR and ADM groups showed significantly higher SBP levels than WKY rats （P〈0.05）, and at 24 weeks, SBP was significantly lower in ADM group than in SHR group （P〈0.05）. The intima thickness/lumen diameter （IT/LD） ratio of the renal arterioles increased in both SHR and ADM groups at 16 and 24 weeks as compared with that of WKY rats （P〈0.05）, and for arterioles with an outer diameter 〈40 btm, the IT/LD ratio was significantly lower at 24 weeks in ADM group than in SHR group （P〈0.05）. The renal expression of p-ERK1/2, which increased significantly in SHR and ADM groups at 16 and 24 weeks （P〈0.05）, was significantly lower in ADM group than in SHR group at 24 weeks （P〈0.05）. Conclusions Long-term ADM treatment can control SPB elevation in SHR rats and reduce renal arteriole remodeling by inhibiting the phosphorylation of ERK1/2.