Urinary cytokine profiles according to the site of blockade of the renin-angiotensin system in nephrectomized rats

Abstract Introduction: It is still unknown how the pharmacological inhibition of the Renin Angiotensin System (RAS) impacts the levels of inflammation and fibrosis biomarkers. Objective: This study sought to evaluate the effect of enalapril, candesartan and aliskiren on urinary levels of cytokines in a model of chronic kidney disease (CKD). Methods: Male Wistar rats were submitted to surgical removal of ¾ of renal parenchyma to induce CKD (¾ nephrectomy), or subjected to sham surgery (control). Animals were then randomized into five groups: Sham surgery receiving vehicle; ¾ Nephrectomy receiving vehicle; ¾ Nephrectomy receiving enalapril (10 mg/kg); ¾ Nephrectomy receiving candesartan (10 mg/kg) and ¾ Nephrectomy receiving aliskiren (10 mg/kg). Urine output, water intake, mean arterial pressure (MAP) and urinary concentrations of creatinine, urea, albuminuria, Na+, K+, interleukin (IL) -1β, IL-6, IL-10 and transforming growth factor beta (TGF-β) were measured. Results: Nephrectomy significantly impaired renal function, increased MAP and altered the levels of all evaluated cytokines in urine. Enalapril, candesartan and aliskiren improved renal function and decreased MAP and IL-6 when compared to vehicle-treated nephrectomized group. Candesartan and aliskiren decreased IL-1β, while only candesartan reduced TGF-β and only aliskiren increased IL-10. Conclusion: Enalapril, candesartan and aliskiren presented similar effects on improving renal function and reducing MAP and urinary levels of IL-6 in rats with CKD. On the other hand, cytokine profile differed according to the treatment, suggesting that differential mechanisms were triggered in response to the site of RAS blockade.

引言：目前尚不清楚肾素-血管紧张素系统（Renin Angiotensin System, RAS）的药物抑制作用对炎症与纤维化生物标志物水平的影响机制。
研究目的：本研究旨在评估依那普利（enalapril）、坎地沙坦（candesartan）与阿利吉仑（aliskiren）对慢性肾脏病（chronic kidney disease, CKD）模型大鼠尿液细胞因子水平的影响。
方法：将雄性Wistar大鼠通过手术切除3/4肾实质以构建慢性肾脏病模型（3/4肾切除术），或仅实施假手术作为对照。随后将实验动物随机分为5组：假手术对照组给予赋形剂；3/4肾切除术模型组给予赋形剂；3/4肾切除术模型组分别给予依那普利（10 mg/kg）、坎地沙坦（10 mg/kg）与阿利吉仑（10 mg/kg）。测定各组大鼠的尿量、摄水量、平均动脉压（mean arterial pressure, MAP）以及尿液中肌酐、尿素、白蛋白尿、钠离子（Na+）、钾离子（K+）、白细胞介素（interleukin, IL）-1β、IL-6、IL-10与转化生长因子β（transforming growth factor beta, TGF-β）的浓度。
结果：肾切除术可显著损伤肾功能、升高平均动脉压，并改变尿液中所有检测细胞因子的水平。与赋形剂处理的肾切除模型组相比，依那普利、坎地沙坦与阿利吉仑均可改善肾功能、降低平均动脉压与尿液IL-6水平。坎地沙坦与阿利吉仑可降低尿液IL-1β水平，仅坎地沙坦可减少尿液TGF-β浓度，仅阿利吉仑可升高尿液IL-10水平。
结论：依那普利、坎地沙坦与阿利吉仑在改善慢性肾脏病大鼠肾功能、降低平均动脉压与尿液IL-6水平方面具有相似的作用效果。但不同药物处理后的细胞因子谱存在差异，提示针对肾素-血管紧张素系统不同位点的阻断可触发差异化的作用机制。