坎地沙坦对盐负荷高血压大鼠肾脏肾素-血管紧张素系统表达的影响

Effects of candesartan on expression of the renal renin-angiotensin system in salt-loaded stroke-prone spontaneously hypertensive rats

目的探讨血管紧张素Ⅱ(AngⅡ)受体拮抗剂坎地沙坦对盐负荷易卒中自发性高血压大鼠(SHRSP)肾脏肾素-血管紧张素系统(RAS)表达的影响及其肾脏保护作用。方法建立8%高盐Wistar-Kyoto(WKY)大鼠和SHRSP模型。高盐WKY大鼠作为对照组,高盐SHRSP随机分为3组:高盐SHRSP组、坎地沙坦给药组和三氯噻嗪给药组。2wk末检测尿(白)蛋白排泄、肾脏AngⅡ水平,RT-PCR方法检测肾皮质RAS组分:血管紧张素原、肾素、组织蛋白酶D、血管紧张素转换酶、AT1和AT2受体mRNA表达,以及转化生长因子β1(TGF-β1)、骨桥蛋白和Ⅳ型胶原mRNA的表达。结果肾皮质RAS各组分mRNA表达,高盐SHRSP组高于高盐WKY组(P<0.01),坎地沙坦下调了高盐SHRSP肾皮质RAS组分mRNA的表达,降低了肾脏AngⅡ水平(P<0.01),抑制了肾皮质TGF-β1、骨桥蛋白和Ⅳ型胶原mRNA的表达(P<0.01),减少了尿(白)蛋白的排泄(P<0.01)。而等效降压剂量的TCM仅对血管紧张素原和ACE mRNA表达有抑制作用(P<0.05),对肾组织AngⅡ无明显抑制作用(P>0.05);TCM虽对TGF-β1和Ⅳ型胶原mRNA表达有抑制作用(P<0.05),对高盐SHRSP尿(白)蛋白排泄也无明显影响(P>0.05)。结论坎地沙坦对盐负荷SHRSP具有降压以外的肾脏保护作用,其机制与抑制肾脏RAS组分表达有关。

Aim To investigate the effects of an angiotensin Ⅱ（ AngⅡ） receptor blocker （ ARB）, candesartan, on expression of the renal renin-angiotensin system （RAS） and its renoprotection in salt-loaded stroke-prone spontaneously hypertensive rats （SHRSP） in vivo. Methods 12-week-old salt-loaded SHRSP were treated with candesartan （ 1.0 mg·kg^-1·d^-1 ） or a diuretic, trichlormethiazide （TCM, 1.6 mg·kg^-1·d^-1） or no treatment （n = 6 in each group） for 2 weeks. Age-matched salt-loaded WKY rats were served as control（ n = 6）. Urinary albumin, protein excretion and renal Ang Ⅱ were measured with ELISA, Bradford assay and radioimmunology methods separately. The renal cortex mRNA expression of RAS components, including angiotensinogen, renin, cathepsin D, ACE, AT1R and AT2R was detected by RT-PCR. Renal cortex mRNA expression of TGF-β1 , osteopontin and type Ⅳ collogen was detected with RT-PCR. Results The mRNA expression of RAS components, TGF-β1, osteopontin and type Ⅳ collogen was significantly up - regulated in salt-loaded SHRSP compared With salt-loaded WKY rats （ P 〈 0. 01 ）. Renal Ang Ⅲ levels and urinary albumin and protein excretion were markedly increased in salt-loaded SHRSP（ P 〈 0. 01 ）. Candesartan and TCM have the effect to reduce systolic blood pressure at similar level . Candesartan signifi - cantly downregulated mRNA levels of RAS components, TGF-β1, osteopontin and type Ⅳ collogen in salt-loaded SHRSP（ P 〈 0. 01 ） while TCM only downregulated mRNA levels of angiotensinogen, ACE, TGF-β1 and type Ⅳ collogen （ P 〈 0. 05 ）. Candesartan, but not TCM, markedly decreased renal Ang Ⅱ levels and urinary albumin and protein excretion （P 〈 0.01 ）. Conclusion Candesartan exerts renoprotective effects independently of blood pressure reduction by suppressing renal expression of RAS components in salt-loaded SHRSP.