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Review
. 2023 Feb 8;24(4):3427.
doi: 10.3390/ijms24043427.

Endothelin Receptor Antagonists in Kidney Disease

Irene Martínez-Díaz  1 , Nerea Martos  1 , Carmen Llorens-Cebrià  1 , Francisco J Álvarez  2 , Patricia W Bedard  2 , Ander Vergara  1 , Conxita Jacobs-Cachá  1 , Maria José Soler  1
Affiliations
Review

Endothelin Receptor Antagonists in Kidney Disease

Irene Martínez-Díaz et al. Int J Mol Sci. .

Abstract

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.

Keywords: atrasentan; endothelin; endothelin receptor antagonists (ERAs); kidney disease; sparsentan.

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Conflict of interest statement

F.J.Á. and P.W.B. are employees of Travere Therapeutics. A.V. reports personal fees from MUNDIPHARMA, and non-financial support from MUNDIPHARMA, SANOFI and NOVONORDISK outside this work. C.J.C. declares travel support and a research grant from TRAVERE THERAPEUTICS outside this work. M.J.S. reports grants from BOEHRINGER, personal fees from NOVONORDISK, JANSSEN, BOHERINGER ASTRAZENECA, FRESENIUS, MUNDIPHARMA, PFIZER, ICU, GE Healthcare BAYER, TRAVERE THERAPEUTICS and VIFOR, and non-financial support from ELI LILLY and ESTEVE outside this work.

Figures

Figure 1
Figure 1
Scheme of the endothelin system. ET-1 acts thought its binding to ETA and ETB producing opposite effects in the kidney. The effects caused by the activation of ETA are shown in red and the effects of ETB activation are shown in blue. In pathological conditions, the hyperglycaemia, acidosis and the presence of insulin, angiotensin II and proinflammatory cytokines causes the increase of ET-1 concentration, which produces deleterious effects on renal function, such as vasoconstriction and endothelial damage, inflammation, fibrosis, podocyte damage or albuminuria.
See this image and copyright information in PMC

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