发现内皮素(ET)在继发于高血糖的肾脏疾病中增加,高血压,酸中毒,以及胰岛素或促炎细胞因子的存在。在这种情况下,ET,通过内皮素受体A型(ETA)激活,引起传入小动脉的持续血管收缩,产生有害作用,如超滤,足细胞损伤,蛋白尿和,最终,GFR下降。因此,内皮素受体拮抗剂(ERA)已被提出作为减少蛋白尿和减缓肾脏疾病进展的治疗策略。临床前和临床证据表明,ERA的给药可减少肾脏纤维化,炎症和蛋白尿。目前,许多ERA治疗肾脏疾病的功效正在随机对照试验中进行测试;然而,其中一些,比如avosentan和atrasentan,由于与使用相关的不良事件而未商业化。因此,利用电子逆向拍卖的保护特性,已经提出使用ETA受体特异性拮抗剂和/或将其与钠-葡萄糖协同转运蛋白2抑制剂(SGLT2i)组合以预防水肿,与ERA相关的主要有害影响。也正在评估使用双重血管紧张素II型1/内皮素受体阻滞剂(sparsentan)来治疗肾脏疾病。这里,我们回顾了已开发的主要ERA及其肾脏保护作用的临床前和临床证据.此外,我们概述了将ERA纳入肾脏疾病治疗的新策略.
Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the endothelin receptor type A (ETA) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ETA receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment.