Tempol通过降低氧化应激下调肥胖相关性高血压大鼠肾脏AT_1受体表达

Tempol improves AT_1 receptor expression in kidney of obese-related hypertensive rats by reducing oxidative stress

目的 探讨Tempol通过降低氧化应激，下调肥胖Zucker大鼠肾脏AT1受体的表达及功能。 方法 选用12周龄的雄性瘦型（体质量260-280 g）及肥胖型（体质量400-420 g）Zucker大鼠各10只，实验分为瘦型对照组、肥胖对照组、瘦型处理组及肥胖处理组。对照组给予正常饮水，处理组给予Tempol（1.0 mmol/L）处理，4周后通过血糖仪测定血糖，ELISA法测定血清胰岛素，血浆生化仪测定甘油三酯及总胆固醇，无创鼠尾侧压仪测定血压，比较4组Zucker大鼠一般生理参数。ELISA法测定4组大鼠血清氧化应激（MDA、SOD）水平变化。通过肾上腺动脉灌注AT1受体阻断剂（坎地沙坦）测定4组大鼠尿钠排泄，在体观察肾脏AT1受体功能。qRT-PCR检测大鼠肾脏AT1的mRNA表达，Western blot法测定大鼠肾脏AT1受体的蛋白表达。 结果 肥胖Zucker大鼠体质量、肾脏大小、甘油三酯、胆固醇、空腹血糖、胰岛素及血压较瘦型Zucker大鼠均显著升高（P〈0.05）。肾上腺动脉灌注坎地沙坦后，肥胖Zucker大鼠的排钠利尿反应性明显强于瘦型大鼠[尿流速：（4.90±0.40） vs （13.30±0.78） μL/min，P〈0.05；尿钠排泄率：（0.44±0.07） vs （1.63±0.18） μmol/min，P〈0.05]，同时AT1受体的mRNA及蛋白表达在肥胖Zucker大鼠肾脏也显著高于瘦型大鼠[mRNA：（0.38±0.11） vs （0.88±0.21），P〈0.05；蛋白：（0.85±0.03） vs （1.26±0.05），P〈0.05]。通过Tempol处理4周后，可明显改善肥胖Zucker大鼠上述变化，而Tempol对瘦型Zucker大鼠无相应作用。 结论 Tempol通过降低氧化应激下调肥胖相关性高血压Zucker大鼠肾脏AT1受体的表达及功能。

Objective To determine the effect of tempol on the expression and function of renal angiotensin receptor type-1 （AT1 receptor） in the kidney of obese Zucker rats. Methods Ten 12-week-old male lean Zucker （260 to 280 g） and 10 male obese Zucker rats at the same age （400 to 420 g） were divided into 4 groups, that is, lean control, obese control, lean tempol group and obese tempol group with 5 rats in each group. The rats from the control groups were given normal drinking water for 4 weeks, while the rats of tempol treatment received drinking water containing 1.0 mmol/L tempol for same duration. Their physiological parameters, including blood pressure, blood glucose, serum insulin, serum total cholesterol and triglyceride were measured. The serum levels of MDA and SOD were measured by ELISA. The effect of the AT1 receptor antagonist candesartan on natriuresis and diuresis in the lean and obese Zucker rats were determined by suprarenal artery administration. The mRNA and protein levels of AT1 receptor in the renal tissue were measured by qRT-PCR and Western blotting, respectively. Results As compared with lean control rats, the obese control rats had significantly higher body weight, kidney weight, fasting blood glucose, and serum levels of total cholesterol, triglyceride and insulin （P〈0.05）. After infusion of the AT1 receptor antagonist candesartan, the natriuresis and diuresis were significantly stronger in obese Zucker rats （urine flow： 4.90±0.40 vs 13.30±0.78, P〈0.05; urine sodium excretion：0.44±0.07 vs 1.63±0.18,P〈0.05）. Moreover, the expression of AT1 receptor at mRNA and protein levels were obvious higher in obese than lean rats （0.38±0.11 vs 0.88±0.21, P〈0.05; 0.85±0.03 vs 1.26±0.05, P〈0.05）. All of the above-mentioned abnormalities were reversed in obese Zucker rats by 4-week tempol treatment, but not in lean Zucker rats. Conclusion Tempol reduces oxidative stress and downregulates the expression and function of AT1 receptor in the kidney of obese-related hypertensive Zucker rats.