Jin Chunhua, O'Boyle Sean, Kleven Daniel T, Pollock Jennifer S, Pollock David M, White John J
Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Clin Exp Pharmacol Physiol. 2014 Aug;41(8):579-88. doi: 10.1111/1440-1681.12250.
Metabolic syndrome (MetS) and chronic kidney disease are global health issues. Metabolic syndrome induces hypertension and commonly results in renal damage. The optimal therapy for hypertension in MetS is unknown. Thiazide diuretics are first-line therapy; however, these drugs may have untoward effects. In the present study we investigated the effects of azilsartan (AZL), chlorthalidone (CLTD) and their combination on blood pressure and renal injury in a rodent model with features of MetS. Dahl salt-sensitive rats were fed high-fat (36% fat), high-salt (4% NaCl) diet. Groups were then treated with vehicle, AZL (3 mg/kg per day), CLTD (5 mg/kg per day) or AZL + CLTD. Mean arterial pressure was recorded continuously by telemetry. After 26 days, rats were killed humanely and their kidneys were harvested for histology. Both AZL and CLTD attenuated the rise in blood pressure compared with vehicle and the combination further reduced blood pressure compared with CLTD alone. All treatments reduced proteinuria and albuminuria. Nephrinuria was prevented only in groups treated with AZL. Nephrinuria was 57% lower and proteinuria was 47% lower with combination therapy compared with AZL alone. All treatments reduced the number of inflammatory cells in the kidney. In conclusion, in our model, AZL and CLTD lower blood pressure and exhibit renal protective effects. Treatment with AZL offers additional protection, as evidenced by lower nephrinuria and plasma monocyte chemoattractant protein-1 levels. Combination therapy afforded the greatest protective effects and may be the best choice for hypertensive therapy in MetS.
代谢综合征（MetS）和慢性肾脏病是全球性的健康问题。代谢综合征会引发高血压，并常常导致肾损伤。代谢综合征患者高血压的最佳治疗方法尚不清楚。噻嗪类利尿剂是一线治疗药物；然而，这些药物可能有不良作用。在本研究中，我们在具有代谢综合征特征的啮齿动物模型中研究了阿齐沙坦（AZL）、氯噻酮（CLTD）及其联合用药对血压和肾损伤的影响。给 Dahl 盐敏感大鼠喂食高脂肪（36%脂肪）、高盐（4%氯化钠）饮食。然后将大鼠分为几组，分别给予赋形剂、AZL（每天 3 毫克/千克）、CLTD（每天 5 毫克/千克）或 AZL + CLTD 进行治疗。通过遥测技术连续记录平均动脉压。26 天后，对大鼠实施安乐死并摘取肾脏进行组织学检查。与赋形剂相比，AZL 和 CLTD 均能减轻血压升高，且联合用药与单独使用 CLTD 相比能进一步降低血压。所有治疗均能减少蛋白尿和白蛋白尿。仅在接受 AZL 治疗的组中预防了肾损伤。与单独使用 AZL 相比，联合治疗使肾损伤降低了 57%，蛋白尿降低了 47%。所有治疗均减少了肾脏中的炎症细胞数量。总之，在我们的模型中，AZL 和 CLTD 可降低血压并具有肾脏保护作用。AZL 治疗提供了额外的保护，较低的肾损伤和血浆单核细胞趋化蛋白-1 水平证明了这一点。联合治疗提供了最大的保护作用，可能是代谢综合征高血压治疗的最佳选择。
