Neuhofer W, Pittrow D
Department of Internal Medicine, University of Munich, Munich, Germany.
Eur J Clin Invest. 2009 Jun;39 Suppl 2:50-67. doi: 10.1111/j.1365-2362.2009.02121.x.
Endothelin (ET) is a potent vasoconstrictory peptide with proinflammatory and profibrotic properties that exerts its biological effects through two pharmacologically distinct receptor subtypes, namely ET(A) and ET(B). In addition to its substantial contribution to normal renal function, a large body of evidence suggests that derangement of the renal ET system is involved in the initiation and progression of chronic kidney disease (CKD) in diabetes, hypertension and glomerulonephritis. Thus, the use of ET receptor antagonists (ERAs) may offer potential novel treatment strategies in CKD. Recent literature on the role of the renal ET system in the healthy kidney was reviewed. In addition, an unbiased PubMed search was performed for studies published during the last 5 years that addressed the effects of ERAs in CKD. A particular objective was to extract information regarding whether selective or nonselective ERAs may have therapeutic potential in humans. ET-1 acts primarily as an autocrine or paracrine factor in the kidney. In normal physiology, ET-1 promotes diuresis and natriuresis by local production and action through ET(B) receptors in the renal medulla. In pathology, ET-1 mediates vasoconstriction, mesangial-cell proliferation, extracellular matrix production and inflammation, effects that are primarily conveyed by ET(A) receptors. Results obtained in animal models and in humans with the use of ERAs in CKD are encouraging; nevertheless, it is still under debate which receptor subtype should be targeted. According to most studies, selective inhibition of ET(A) receptors appears superior compared with nonselective ERAs because this approach does not interfere with the natriuretic, antihypertensive and ET clearance effects of ET(B) receptors. Although preliminary data in humans are promising, the potential role of ERAs in patients with CKD and the question of which receptor subtype should be targeted can only be clarified in randomized clinical trials.
内皮素（ET）是一种具有促炎和促纤维化特性的强效血管收缩肽，它通过两种药理学上不同的受体亚型，即ET(A)和ET(B)发挥其生物学效应。除了对正常肾功能有重要贡献外，大量证据表明，肾脏ET系统紊乱参与了糖尿病、高血压和肾小球肾炎所致慢性肾脏病（CKD）的发生和发展。因此，使用ET受体拮抗剂（ERA）可能为CKD提供潜在的新治疗策略。本文综述了关于肾脏ET系统在健康肾脏中作用的近期文献。此外，还对过去5年发表的关于ERA对CKD影响的研究进行了无偏倚的PubMed检索。一个特别的目标是提取有关选择性或非选择性ERA在人类中是否可能具有治疗潜力的信息。ET-1在肾脏中主要作为自分泌或旁分泌因子起作用。在正常生理情况下，ET-1通过在肾髓质中局部产生并通过ET(B)受体起作用来促进利尿和利钠。在病理情况下，ET-1介导血管收缩、系膜细胞增殖、细胞外基质产生和炎症，这些效应主要由ET(A)受体传导。在动物模型和CKD患者中使用ERA所获得的结果令人鼓舞；然而，仍在争论应靶向哪种受体亚型。根据大多数研究，与非选择性ERA相比，选择性抑制ET(A)受体似乎更具优势，因为这种方法不会干扰ET(B)受体的利钠、降压和ET清除作用。尽管人类的初步数据很有前景，但ERA在CKD患者中的潜在作用以及应靶向哪种受体亚型的问题，只有在随机临床试验中才能得到阐明。
