Addition of ETA receptor blockade increases renoprotection provided by renin-angiotensin system blockade in 5/6 nephrectomized Ren-2 transgenic rats
Addition of ETA receptor blockade increases renoprotection provided by renin-angiotensin system blockade in 5/6 nephrectomized Ren-2 transgenic rats
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DOI：
10.1016/j.lfs.2013.12.018
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发表时间：
2014-11-24
期刊：
影响因子：
6.1
通讯作者：
Vaneckova, Ivana
中科院分区：
文献类型：
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作者：
Chabova, Vera Certikova;Vernerova, Zdenka;Vaneckova, Ivana
目的：有证据表明，除了高血压和肾素-血管紧张素系统(RAS)的高活性外，肾内内皮素(ET)系统的活性增强也参与了慢性肾脏疾病(CKD)的病理生理和进展。这促使我们研究在标准的RAS阻断的基础上加用A型ET受体(ETA)阻断是否可以减缓这一进展。主要方法：5/6肾切除(5/6 NX)后的REN-2转基因大鼠(TGR)作为CKD的模型。血管紧张素转换酶抑制剂(曲多普利，6 mg/L饮用水)和血管紧张素Ⅱ1型受体阻滞剂(氯沙坦，100 mg/L饮用水)联合应用抑制RAS。或者，在联合的RAS阻滞剂中加入ETA受体阻滞剂(阿特拉森坦，饮用水中5 mg·kg(-1)·day(-1))。随访期为5/6NX后44周。主要结果：无论采用哪种治疗方案，大鼠的存活率均有所提高，但在5/6NX后36周，单独应用RAS的有效率显著降低：最终存活率为65%，明显低于RAS和ETA受体联合阻断的91%。加入ETA阻滞剂不影响SOP，蛋白尿和肾小球损害进一步减少。意义：我们的数据显示，与单独使用RAS阻断剂相比，联合应用RAS和ETA受体阻断剂对5/6 NX TGR患者的存活率和CKD的进展有更多的有利影响。(C)2013年提交人。由爱思唯尔公司出版。
Aims: There is evidence that in addition to hypertension and hyperactivity of the renin-angiotensin system (RAS), enhanced intrarenal activity of endothelin (ET) system contributes to the pathophysiology and progression of chronic kidney disease (CKD). This prompted us to examine if this progression would be alleviated by addition of type A ET receptor (ETA) blockade to the standard blockade of RAS.Main methods: Ren-2 transgenic rats (TGR) after 5/6 renal ablation (5/6 NX) served as a model of CKD. For RAS inhibition a combination of angiotensin-converting enzyme inhibitor (trandolapril, 6 mg/L drinking water) and angiotensin II type 1 receptor blocker (Iosartan, 100 mg/L drinking water) was used. Alternatively, ETA receptor blocker (atrasentan, 5 mg.kg(-1).day(-1) in drinking water) was added to the combined RAS blockade. The follow-up period was 44 weeks after 5/6 NX. and the rats' survival rate, systolic blood pressure (SOP), proteinuria and indices of renal glomerular damage were evaluated.Key findings: The survival rate was at first improved, by either therapeutic regime, however, the efficiency of RAS blockade alone considerably decreased 36 weeks after 5/6 NX: final survival rate of 65% was significantly lower than 91% achieved with combined RAS and ETA receptor blockade. SOP was not affected by the addition of ETA blockade while proteinuria and renal glomerular damage were further reduced.Significance: Our data show that a combined RAS and ETA receptor blockade exhibits additional beneficial effects on survival rate and the progression of CKD in 5/6 NX TGR, as compared with RAS inhibition alone. (C) 2013 The Authors. Published by Elsevier Inc.