Barton Matthias, Sorokin Andrey
Molecular Internal Medicine, University of Zurich, Zurich, Switzerland.
Department of Medicine, Kidney Disease Center, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI.
Semin Nephrol. 2015 Mar;35(2):156-67. doi: 10.1016/j.semnephrol.2015.02.005.
Endothelin-1 (ET-1) is a 21-amino acid peptide with mitogenic and powerful vasoconstricting properties. Under healthy conditions, ET-1 is expressed constitutively in all cells of the glomerulus and participates in homeostasis of glomerular structure and filtration function. Under disease conditions, increases in ET-1 are critically involved in initiating and maintaining glomerular inflammation, glomerular basement membrane hypertrophy, and injury of podocytes (visceral epithelial cells), thereby promoting proteinuria and glomerulosclerosis. Here, we review the role of ET-1 in the function of glomerular endothelial cells, visceral (podocytes) and parietal epithelial cells, mesangial cells, the glomerular basement membrane, stromal cells, inflammatory cells, and mesenchymal stem cells. We also discuss molecular mechanisms by which ET-1, predominantly through activation of the ETA receptor, contributes to injury to glomerular cells, and review preclinical and clinical evidence supporting its pathogenic role in glomerular injury in chronic renal disease. Finally, the therapeutic rationale for endothelin antagonists as a new class of antiproteinuric drugs is discussed.
内皮素-1（ET-1）是一种具有促有丝分裂和强大血管收缩特性的21个氨基酸的肽。在健康状态下，ET-1在肾小球的所有细胞中组成性表达，并参与肾小球结构和滤过功能的稳态。在疾病状态下，ET-1的增加在启动和维持肾小球炎症、肾小球基底膜肥大以及足细胞（脏层上皮细胞）损伤中起关键作用，从而促进蛋白尿和肾小球硬化。在此，我们综述ET-1在肾小球内皮细胞、脏层（足细胞）和壁层上皮细胞、系膜细胞、肾小球基底膜、基质细胞、炎症细胞和间充质干细胞功能中的作用。我们还讨论了ET-1主要通过激活ETA受体导致肾小球细胞损伤的分子机制，并综述支持其在慢性肾病肾小球损伤中致病作用的临床前和临床证据。最后，讨论了内皮素拮抗剂作为一类新型抗蛋白尿药物的治疗原理。
