Addition of Endothelin A-Receptor Blockade Spoils the Beneficial Effect of Combined Renin-Angiotensin and Soluble Epoxide Hydrolase Inhibition: Studies on the Course of Chronic Kidney Disease in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats.
Addition of Endothelin A-Receptor Blockade Spoils the Beneficial Effect of Combined Renin-Angiotensin and Soluble Epoxide Hydrolase Inhibition: Studies on the Course of Chronic Kidney Disease in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats.
复制标题
添加内皮素 A 受体阻断会破坏肾素-血管紧张素和可溶性环氧化物水解酶联合抑制的有益效果：5/6 肾切除 Ren-2 转基因高血压大鼠慢性肾病病程的研究。
DOI：
10.1159/000504137
复制
发表时间：
2019
影响因子：
2.8
通讯作者：
Vaněčková,Ivana
中科院分区：
文献类型：
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作者：
ČertíkováChábová,Věra;Kujal,Petr;Vaňourková,Zdeňka;Škaroupková,Petra;Sadowski,Janusz;Kompanowska-Jezierska,Elzbieta;Tesař,Vladimír;Hammock,Bruce;Imig,John;Maxová,Hana;Červenka,Luděk;Vaněčková,Ivana
Ren-2转基因高血压大鼠（TGR）5/6肾切除术（5/6 NX）后的既往研究表明，除了药物阻断肾素-血管紧张素系统（RAS）外，还通过阻断可溶性环氧化物水解酶（sEH）（一种负责降解EET的酶）增加肾组织环氧二十碳三烯酸（EET）水平，并且内皮素A型（ETA）受体阻断剂延缓慢性肾病（CKD）的进展。这促使我们评估在标准的RAS复合阻断剂基础上加用sEH抑制剂和ET A受体拮抗剂是否能缓解这种进展（血管紧张素转换酶抑制剂加血管紧张素II 1型受体阻滞剂）治疗已建立CKD的大鼠。方法在TGR中5/6 NX后6周开始治疗方案，结果在RAS阻断的基础上加用sEH抑制剂可提高生存率，进一步减少蛋白尿和肾小球及肾小管间质损伤，并减弱了肌酐清除率的下降-所有这些与单独使用RAS阻断剂治疗的5/6 NX TGR相比。此外，ET A受体拮抗剂的组合RAS和sEH封锁不仅没有提供额外的肾保护，但令人惊讶的是，也取消了有益的影响，加入sEH抑制剂的RAS blocking.ConclusionThese数据表明，药理学策略，联合收割机的RAS和sEH的封锁可能是一种新的工具，以打击慢性肾脏病的进展。任何进一步扩展这种治疗方案的尝试都应极其谨慎。
IntroductionPrevious studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ET A) receptor blockade retards chronic kidney disease (CKD) progression. This prompted us to evaluate if this progression will be alleviated by the addition of sEH inhibitor and ET A receptor antagonist to the standard complex blockade of RAS (angiotensin-converting enzyme inhibitor plus angiotensin II type 1 receptor blocker) in rats with established CKD.MethodsThe treatment regimens were initiated 6 weeks after 5/6 NX in TGR, and the follow-up period was 60 weeks.ResultsThe addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance–all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ET A receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, also abolished the beneficial effects of adding sEH inhibitor to the RAS blockade.ConclusionThese data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to further extend this therapeutic regimen should be made with extreme caution.