Division of Nephrology, University of Utah Health, Salt Lake City, UT, U.S.A.
Travere Therapeutics, Inc., San Diego, CA, U.S.A.
Clin Sci (Lond). 2024 Jun 5;138(11):645-662. doi: 10.1042/CS20240249.
Simultaneous inhibition of angiotensin II AT1 and endothelin ETA receptors has emerged as a promising approach for treatment of chronic progressive kidney disease. This therapeutic approach has been advanced by the introduction of sparsentan, the first dual AT1 and ETA receptor antagonist. Sparsentan is a single molecule with high affinity for both receptors. It is US Food and Drug Administration approved for immunoglobulin A nephropathy (IgAN) and is currently being developed as a treatment for rare kidney diseases, such as focal segmental glomerulosclerosis. Clinical studies have demonstrated the efficacy and safety of sparsentan in these conditions. In parallel with clinical development, studies have been conducted to elucidate the mechanisms of action of sparsentan and its position in the context of published evidence characterizing the nephroprotective effects of dual ETA and AT1 receptor inhibition. This review summarizes this evidence, documenting beneficial anti-inflammatory, antifibrotic, and hemodynamic actions of sparsentan in the kidney and protective actions in glomerular endothelial cells, mesangial cells, the tubulointerstitium, and podocytes, thus providing the rationale for the use of sparsentan as therapy for focal segmental glomerulosclerosis and IgAN and suggesting potential benefits in other renal diseases, such as Alport syndrome.
同时抑制血管紧张素 II AT1 和内皮素 ETA 受体已成为治疗慢性进行性肾病的一种有前途的方法。这种治疗方法因引入首个双重 AT1 和 ETA 受体拮抗剂 sparsentan 而得到推进。sparsentan 是一种对两种受体都具有高亲和力的单一分子。它已获得美国食品和药物管理局批准用于治疗免疫球蛋白 A 肾病 (IgAN)，目前正在开发用于治疗罕见的肾脏疾病，如局灶节段性肾小球硬化症。临床研究表明 sparsentan 在这些疾病中的疗效和安全性。随着临床开发的进行，已经进行了研究以阐明 sparsentan 的作用机制及其在发表的特征描述双重 ETA 和 AT1 受体抑制的肾保护作用的证据中的地位。这篇综述总结了这方面的证据，记录了 sparsentan 在肾脏中的有益的抗炎、抗纤维化和血液动力学作用，以及在肾小球内皮细胞、系膜细胞、肾小管间质和足细胞中的保护作用，从而为 sparsentan 作为局灶节段性肾小球硬化症和 IgAN 的治疗方法提供了依据，并提示其在其他肾脏疾病（如 Alport 综合征）中可能具有潜在益处。
