Molecular Internal Medicine, University of Zürich, Zürich, Switzerland.
INSERM and Université Paris Descartes, Sorbonne Paris Cité, Paris Cardiovascular Centre, Paris, France.
Clin Kidney J. 2012 Feb;5(1):17-27. doi: 10.1093/ckj/sfs001.
In the past decade, research has advanced our understanding how endothelin contributes to proteinuria and glomerulosclerosis. Data from pre-clinical and clinical studies now provide evidence that proteinuric diseases such as focal segmental glomerulosclerosis and diabetic nephropathy as well as hypertension nephropathy are sensitive to treatment with endothelin receptor antagonists (ERAs). Like blockade of the renin-angiotensin system, ERA treatment-under certain conditions-may even cause disease regression, effects that could be achieved on top of renin-angiotensin-aldosterone system blockade, suggesting independent therapeutic mechanisms by which ERAs convey nephroprotection. Beneficial effects of ERAs on podocyte function, which is essential to maintain the glomerular filtration barrier, have been identified as one of the key mechanisms by which inhibition of the endothelin ETA receptor ameliorates renal structure and function. In this article, we will review pre-clinical studies demonstrating a causal role for endothelin in proteinuric chronic kidney disease (with a particular focus on functional and structural integrity of podocytes in vitro and in vivo). We will also review the evidence suggesting a therapeutic benefit of ERA treatment on the functional integrity of podocytes in humans.
在过去的十年中，研究已经深入了解了内皮素如何导致蛋白尿和肾小球硬化。来自临床前和临床研究的数据现在提供了证据，表明蛋白尿疾病（如局灶节段性肾小球硬化和糖尿病肾病以及高血压肾病）对内皮素受体拮抗剂（ERAs）的治疗敏感。像阻断肾素-血管紧张素系统一样，在某些情况下，ERA 治疗甚至可以导致疾病逆转，这些效果可以在肾素-血管紧张素-醛固酮系统阻断的基础上实现，这表明 ERAs 通过独立的治疗机制发挥肾脏保护作用。已经确定 ERAs 对足细胞功能的有益影响是维持肾小球滤过屏障所必需的，这是抑制内皮素 ETA 受体改善肾脏结构和功能的关键机制之一。在本文中，我们将回顾临床前研究，这些研究证明了内皮素在蛋白尿性慢性肾脏病中的因果作用（特别关注足细胞的功能和结构完整性，无论是在体外还是在体内）。我们还将回顾表明 ERA 治疗对人类足细胞功能完整性具有治疗益处的证据。
