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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.<\/jats:p>","DOI":"10.3390\/ijms24043427","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T01:59:43Z","timestamp":1675907983000},"page":"3427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Endothelin Receptor Antagonists in Kidney Disease"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5849-7900","authenticated-orcid":false,"given":"Irene","family":"Mart\u00ednez-D\u00edaz","sequence":"first","affiliation":[{"name":"Nephrology and Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerea","family":"Martos","sequence":"additional","affiliation":[{"name":"Nephrology and Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3611-1816","authenticated-orcid":false,"given":"Carmen","family":"Llorens-Cebri\u00e0","sequence":"additional","affiliation":[{"name":"Nephrology and Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Travere Therapeutics, Inc., San Diego, CA 92130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia W.","family":"Bedard","sequence":"additional","affiliation":[{"name":"Travere Therapeutics, Inc., San Diego, CA 92130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1926-0147","authenticated-orcid":false,"given":"Ander","family":"Vergara","sequence":"additional","affiliation":[{"name":"Nephrology and Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2518-7847","authenticated-orcid":false,"given":"Conxita","family":"Jacobs-Cach\u00e1","sequence":"additional","affiliation":[{"name":"Nephrology and Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3621-0766","authenticated-orcid":false,"given":"Maria Jos\u00e9","family":"Soler","sequence":"additional","affiliation":[{"name":"Nephrology and Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1139\/Y08-059","article-title":"Endothelin: 20 Years from Discovery to Therapy","volume":"86","author":"Barton","year":"2008","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"C550","DOI":"10.1152\/ajpcell.1985.248.5.C550","article-title":"Characterization of a Coronary Vasoconstrictor Produced by Cultured Endothelial Cells","volume":"248","author":"Hickey","year":"1985","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/332411a0","article-title":"A Novel Potent Vasoconstrictor Peptide Produced by Vascular Endothelial Cells","volume":"332","author":"Yanagisawa","year":"1988","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/ki.1996.56","article-title":"Localization of Endothelin Peptides in Human Kidney","volume":"49","author":"Karet","year":"1996","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1073\/pnas.86.8.2863","article-title":"The Human Endothelin Family: Three Structurally and Pharmacologically Distinct Isopeptides Predicted by Three Separate Genes","volume":"86","author":"Inoue","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S83","DOI":"10.1016\/S0895-7061(01)02074-X","article-title":"Role of Endothelin-1 in Hypertension and Vascular Disease","volume":"14","author":"Schiffrin","year":"2001","journal-title":"Am. J. Hypertens."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.semnephrol.2015.02.002","article-title":"Endothelin Receptors and Their Antagonists","volume":"35","author":"Maguire","year":"2015","journal-title":"Semin. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"F217","DOI":"10.1152\/ajprenal.1990.259.2.F217","article-title":"Renal Microvascular Effects of Endothelin","volume":"259","author":"Edwards","year":"1990","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1093\/ndt\/gfq534","article-title":"Endothelin Type A and B Receptors in the Control of Afferent and Efferent Arterioles in Mice","volume":"26","author":"Schildroth","year":"2011","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"F449","DOI":"10.1152\/ajprenal.1995.269.3.F449","article-title":"Endothelin Receptor MRNA Expression in Renal Medulla Identified by in Situ RT-PCR","volume":"269","author":"Chow","year":"1995","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nrneph.2012.19","article-title":"Glomerular Hyperfiltration: Definitions, Mechanisms and Clinical Implications","volume":"8","author":"Helal","year":"2012","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1681\/ASN.2016060666","article-title":"Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment","volume":"28","author":"Tonneijck","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"872918","DOI":"10.3389\/fendo.2022.872918","article-title":"Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease","volume":"13","author":"Yang","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1161\/01.CIR.0000118499.69469.51","article-title":"Endothelin-A Receptor Antagonism Reduces Blood Pressure and Increases Renal Blood Flow in Hypertensive Patients with Chronic Renal Failure: A Comparison of Selective and Combined Endothelin Receptor Blockade","volume":"109","author":"Goddard","year":"2004","journal-title":"Circulation"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/3-540-32967-6_9","article-title":"Endothelin","volume":"Volume 176","author":"Davenport","year":"2006","journal-title":"The Vascular Endothelium I"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1161\/HYPERTENSIONAHA.110.156570","article-title":"Endothelin-1 Increases Glomerular Permeability and Inflammation Independent of Blood Pressure in the Rat","volume":"56","author":"Saleh","year":"2010","journal-title":"Hypertension"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1139\/Y10-061","article-title":"Darusentan Is a Potent Inhibitor of Endothelin Signaling and Function in Both Large and Small Arteries","volume":"88","author":"Liang","year":"2010","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1681\/ASN.2013080830","article-title":"The Endothelin Antagonist Atrasentan Lowers Residual Albuminuria in Patients with Type 2 Diabetic Nephropathy","volume":"25","author":"Coll","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1016\/S0140-6736(19)30772-X","article-title":"Atrasentan and Renal Events in Patients with Type 2 Diabetes and Chronic Kidney Disease (SONAR): A Double-Blind, Randomised, Placebo-Controlled Trial","volume":"393","author":"Heerspink","year":"2019","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1124\/pr.115.011833","article-title":"Endothelin","volume":"68","author":"Davenport","year":"2016","journal-title":"Pharmacol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"761","DOI":"10.2165\/00003495-200767050-00007","article-title":"Sitaxentan: In Pulmonary Arterial Hypertension","volume":"67","author":"Scott","year":"2007","journal-title":"Drugs"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"824","DOI":"10.3390\/jcm9030824","article-title":"Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy","volume":"9","author":"Enevoldsen","year":"2020","journal-title":"J. Clin. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1681\/ASN.2008050482","article-title":"Avosentan Reduces Albumin Excretion in Diabetics with Macroalbuminuria","volume":"20","author":"Wenzel","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s13075-022-02818-6","article-title":"Zibotentan in Systemic Sclerosis-Associated Chronic Kidney Disease: A Phase II Randomised Placebo-Controlled Trial","volume":"24","author":"Stern","year":"2022","journal-title":"Arthritis Res. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"302","DOI":"10.3389\/fped.2019.00302","article-title":"Bosentan for Treatment of Pediatric Idiopathic Pulmonary Arterial Hypertension: State-of-the-Art","volume":"7","author":"Wang","year":"2019","journal-title":"Front. Pediatr."},{"key":"ref_26","first-page":"272","article-title":"Endothelin System and Therapeutic Application of Endothelin Receptor Antagonists","volume":"10","author":"Mekuria","year":"2021","journal-title":"J. Clin. Exp. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1016\/S0140-6736(22)02034-7","article-title":"Dual Endothelin Antagonist Aprocitentan for Resistant Hypertension (PRECISION): A Multicentre, Blinded, Randomised, Parallel-Group, Phase 3 Trial","volume":"400","author":"Schlaich","year":"2022","journal-title":"Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1021\/jm049548x","article-title":"Dual Angiotensin II and Endothelin A Receptor Antagonists: Synthesis of 2\u2032-Substituted N-3-Isoxazolyl Biphenylsulfonamides with Improved Potency and Pharmacokinetics","volume":"48","author":"Murugesan","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.ekir.2019.12.017","article-title":"Study Design of the Phase 3 Sparsentan Versus Irbesartan (DUPLEX) Study in Patients With Focal Segmental Glomerulosclerosis","volume":"5","author":"Komers","year":"2020","journal-title":"Kidney Int. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"D1307","DOI":"10.1093\/nar\/gkab918","article-title":"NCATS Inxight Drugs: A Comprehensive and Curated Portal for Translational Research","volume":"50","author":"Siramshetty","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1111\/bcp.12064","article-title":"Endothelin Antagonists for Diabetic and Non-Diabetic Chronic Kidney Disease","volume":"76","author":"Kohan","year":"2013","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1177\/1753944710373785","article-title":"Darusentan, a Selective Endothelin A Receptor Antagonist, for the Oral Treatment of Resistant Hypertension","volume":"4","author":"Enseleit","year":"2010","journal-title":"Ther. Adv. Cardiovasc. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1021\/jm960274q","article-title":"Expedited Articles Discovery and Optimization of a Novel Class. of Orally Active Nonpeptidic Endothelin-A Receptor Antagonists","volume":"39","author":"Riechers","year":"1996","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1177\/1753465817696040","article-title":"Ambrisentan: A Review of Its Use in Pulmonary Arterial Hypertension","volume":"11","author":"Risbano","year":"2017","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1111\/jcpt.13481","article-title":"Comparative Assessment of Efficacy and Safety of Ambrisentan and Bosentan in Patients with Pulmonary Arterial Hypertension: A Meta-Analysis","volume":"47","author":"Zhao","year":"2022","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1681\/ASN.2009060593","article-title":"Avosentan for Overt Diabetic Nephropathy","volume":"21","author":"Mann","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s40265-013-0156-6","article-title":"Macitentan: First Global Approval","volume":"74","author":"Patel","year":"2014","journal-title":"Drugs"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1517\/17425255.2015.1000859","article-title":"Pharmacokinetic and Pharmacodynamic Evaluation of Macitentan, a Novel Endothelin Receptor Antagonist for the Treatment of Pulmonary Arterial Hypertension","volume":"11","author":"Sidharta","year":"2015","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.3390\/jcm4061171","article-title":"Endothelin Blockade in Diabetic Kidney Disease","volume":"4","author":"Anguiano","year":"2015","journal-title":"J. Clin. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e14411","DOI":"10.1111\/dme.14411","article-title":"Efficacy and Safety of Endothelin Receptor Antagonists in Type 2 Diabetic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","volume":"38","author":"Zhou","year":"2021","journal-title":"Diabet. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"848389","DOI":"10.3389\/fmed.2022.848389","article-title":"Novel Therapies for Alport Syndrome","volume":"9","author":"Chavez","year":"2022","journal-title":"Front. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1038\/sj.bjc.6602676","article-title":"Specific Inhibition of the Endothelin A Receptor with ZD4054: Clinical and Pre-Clinical Evidence","volume":"92","author":"Morris","year":"2005","journal-title":"Br. J. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0014-5793(96)00213-X","article-title":"In Vitro Characterisation of Ro 46-8443, the First Non-Pep Tide Antagonist Selective for the Endothelin ETB Receptor","volume":"383","author":"Breu","year":"1996","journal-title":"FEBS Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1097\/SHK.0b013e31819e2cbb","article-title":"Inhaled Tezosentan Reduces Pulmonary Hypertension in Endotoxin-Induced Lung Injury","volume":"32","author":"Persson","year":"2009","journal-title":"Shock"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1124\/jpet.108.142976","article-title":"Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist","volume":"327","author":"Iglarz","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s13318-019-00590-8","article-title":"Effect of Multiple-Dose Aprocitentan Administration on the Pharmacokinetics of Midazolam in Healthy Male Subjects","volume":"45","author":"Sidharta","year":"2020","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"949","DOI":"10.2147\/DDDT.S199051","article-title":"Single- and Multiple-Dose Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of the Dual Endothelin Receptor Antagonist Aprocitentan in Healthy Adult and Elderly Subjects","volume":"13","author":"Sidharta","year":"2019","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1038\/ki.2014.143","article-title":"Endothelin and Endothelin Antagonists in Chronic Kidney Disease","volume":"86","author":"Kohan","year":"2014","journal-title":"Kidney Int."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1038\/sj.bjp.0706412","article-title":"ET A and ET B Receptors Differentially Modulate Afferent and Efferent Arteriolar Responses to Endothelin","volume":"146","author":"Inscho","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1161\/01.CIR.84.4.1457","article-title":"Molecular and Cellular Mechanism of Endothelin Regulation: Implications for Vascular Function","volume":"84","author":"Masaki","year":"1991","journal-title":"Circulation"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1152\/jappl.1996.81.4.1510","article-title":"Pulmonary Clearance of Circulating Endothelin-1 in Dogs in Vivo: Exclusive Role of ET(B) Receptors","volume":"81","author":"Dupuis","year":"1996","journal-title":"J. Appl. Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"14367","DOI":"10.1073\/pnas.95.24.14367","article-title":"Endothelin ETA Receptor Blockade Restores NO-Mediated Endothelial Function and Inhibits Atherosclerosis in Apolipoprotein E-Deficient Mice","volume":"95","author":"Barton","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1161\/hh2301.100980","article-title":"Coronary Vasodilation and Improvement in Endothelial Dysfunction with Endothelin ETA Receptor Blockade","volume":"89","author":"Halcox","year":"2001","journal-title":"Circ. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/S0008-6363(01)00469-2","article-title":"Chronic ETA Receptor Blockade Prevents Endothelial Dysfunction of Small Arteries in Apolipoprotein E-Deficient Mice","volume":"53","author":"Barton","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/S0895-7061(97)00405-6","article-title":"Effect of Chronic Treatment with Two Different ETA Selective Endothelin Receptor Antagonists on Blood Pressure and Small Artery Structure of Deoxycorticosterone Acetate (DOCA)-Sant Hypertensive Rats","volume":"11","author":"Li","year":"1998","journal-title":"Am. J. Hypertens."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1369\/jhc.5A6888.2006","article-title":"Distribution of Endothelin Receptor Subtypes ETA and ET B in the Rat Kidney","volume":"54","author":"Wendel","year":"2006","journal-title":"J. Histochem. Cytochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1152\/physrev.1993.73.2.375","article-title":"Endothelins: Muntifunctional Renal Peptides","volume":"73","author":"Simonson","year":"1993","journal-title":"Physiol. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1161\/HYPERTENSIONAHA.119.12105","article-title":"Endothelin: 30 Years from Discovery to Therapy","volume":"74","author":"Barton","year":"2019","journal-title":"Hypertension"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1093\/oxfordjournals.ndt.a092130","article-title":"Functional Endothelin 1 Receptors on Human Glomerular Podocytes and Mesangial Cells","volume":"7","author":"Rebibou","year":"1992","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/ki.1993.263","article-title":"A Specific Endothelin Subtype A Receptor Antagonist Protects against Injury in Renal Disease Progression","volume":"44","author":"Benigni","year":"1993","journal-title":"Kidney Int."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1161\/01.HYP.0000149249.09147.b4","article-title":"Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney after Endothelin Inhibition","volume":"44","author":"Ortmann","year":"2004","journal-title":"Hypertension"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1161\/01.HYP.0000245117.57524.d6","article-title":"Late-Onset Endothelin-A Receptor Blockade Reduces Podocyte Injury in Homozygous Ren-2 Rats despite Severe Hypertension","volume":"48","author":"Kramer","year":"2006","journal-title":"Hypertension"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/S0272-6386(97)90004-4","article-title":"Endothelins in the Normal and Diseased Kidney","volume":"29","author":"Kohan","year":"1997","journal-title":"Am. J. Kidney Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"F579","DOI":"10.1152\/ajprenal.00019.2003","article-title":"Physiology and Pathology of Endothelin-1 in Renal Mesangium","volume":"285","author":"Sorokin","year":"2003","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1038\/ki.1996.397","article-title":"An Orally Active ET(A)\/ET(B) Receptor Antagonist Ameliorates Proteinuria and Glomerular Lesions in Rats with Proliferative Nephritis","volume":"50","author":"Largo","year":"1996","journal-title":"Kidney Int."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1097\/00005344-200206000-00015","article-title":"Endothelin A Receptor Blockade Decreases Expression of Growth Factors and Collagen and Improves Matrix Metalloproteinase-2 Activity in Kidneys from Stroke-Prone Spontaneously Hypertensive Rats","volume":"39","author":"Tostes","year":"2002","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1006\/bbrc.1994.1395","article-title":"Clearance of Circulating Endothelin-1 by Etb Receptors in Rats","volume":"199","author":"Fukuroda","year":"1994","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1172\/JCI119297","article-title":"Endothelin-1 Transgenic Mice Develop Glomerulosclerosis, Interstitial Fibrosis, and Renal Cysts but Not Hypertension","volume":"99","author":"Hocher","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1007\/s00125-010-2021-4","article-title":"Endothelin Receptor A-Specific Stimulation of Glomerular Inflammation and Injury in a Streptozotocin-Induced Rat Model of Diabetes","volume":"54","author":"Saleh","year":"2011","journal-title":"Diabetologia"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1038\/ki.1992.245","article-title":"Endothelin-1 Receptor Antagonist: Effects on Endothelin- and Cyclosporine-Treated Mesangial Cells","volume":"41","author":"Takeda","year":"1992","journal-title":"Kidney Int."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"S232","DOI":"10.1097\/00005344-200036051-00069","article-title":"Adult Human Mesangial Cells (HMCs) Express Endothelin-B-Receptors Which Mediate Endothelin-1-Induced Cell Growth","volume":"36","author":"Orth","year":"2000","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1291\/hypres.21.251","article-title":"ET(A) Receptor Antagonist Ameliorates Nephrosclerosis and Left Ventricular Hypertrophy Induced in Rat by Prolonged Inhibition of Nitric Oxide Synthesis","volume":"21","author":"Nakamura","year":"1998","journal-title":"Hypertens. Res. Clin. Exp."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"F977","DOI":"10.1152\/ajprenal.00182.2018","article-title":"Prevention of the Progression of Renal Injury in Diabetic Rodent Models with Preexisting Renal Disease with Chronic Endothelin A Receptor Blockade","volume":"315","author":"Spires","year":"2018","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1159\/000444719","article-title":"Vascular Endothelial Growth Factor and Podocyte Protection in Chronic Hypoxia: Effects of Endothelin-A Receptor Antagonism","volume":"43","author":"Harvey","year":"2016","journal-title":"Am. J. Nephrol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"F1173","DOI":"10.1152\/ajprenal.00040.2019","article-title":"Sustained, Delayed, and Small Increments in Glomerular Permeability to Macromolecules during Systemic ET-1 Infusion Mediated via the ETa Receptor","volume":"316","author":"Dolinina","year":"2019","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"174445","DOI":"10.1016\/j.ejphar.2021.174445","article-title":"Effects of Systemic and Renal Intramedullary Endothelin-1 Receptor Blockade on Tissue NO and Intrarenal Hemodynamics in Normotensive and Hypertensive Rats","volume":"910","author":"Vaneckova","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"T\u00f6rm\u00e4nen, S., P\u00f6rsti, I., Lakkisto, P., Tikkanen, I., Niemel\u00e4, O., Paavonen, T., Mustonen, J., and Er\u00e4ranta, A. (2017). Endothelin A Receptor Blocker and Calcimimetic in the Adenine Rat Model of Chronic Renal Insufficiency. BMC Nephrol., 18.","DOI":"10.1186\/s12882-017-0742-z"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e6373","DOI":"10.1590\/1414-431x20176373","article-title":"Endothelin-1 Receptor Antagonists Protect the Kidney against the Nephrotoxicity Induced by Cyclosporine-A in Normotensive and Hypertensive Rats","volume":"51","author":"Caires","year":"2018","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1093\/cvr\/cvz260","article-title":"Selective ETA vs. Dual ETA\/B Receptor Blockade for the Prevention of Sunitinib-Induced Hypertension and Albuminuria InWKY Rats","volume":"116","author":"Colafella","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1053\/j.ajkd.2015.10.011","article-title":"Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients with CKD: A Bayesian Network Meta-Analysis of Randomized Clinical Trials","volume":"67","author":"Xie","year":"2016","journal-title":"Am. J. Kidney Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/s41440-018-0116-3","article-title":"Renin-Angiotensin System Inhibitors in Hypertensive Adults with Non-Diabetic CKD with or without Proteinuria: A Systematic Review and Meta-Analysis of Randomized Trials","volume":"42","author":"Mishima","year":"2019","journal-title":"Hypertens. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1053\/j.ajkd.2020.10.006","article-title":"Comparative Effectiveness of Renin-Angiotensin System Inhibitors and Calcium Channel Blockers in Individuals With Advanced CKD: A Nationwide Observational Cohort Study","volume":"77","author":"Fu","year":"2021","journal-title":"Am. J. Kidney Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"F1295","DOI":"10.1152\/ajprenal.00498.2019","article-title":"Beneficial Effect on Podocyte Number in Experimental Diabetic Nephropathy Resulting from Combined Atrasentan and RAAS Inhibition Therapy","volume":"318","author":"Hudkins","year":"2020","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.lfs.2013.12.018","article-title":"Addition of ET A Receptor Blockade Increases Renoprotection Provided by Renin\u2014Angiotensin System Blockade in 5\/6 Nephrectomized Ren-2 Transgenic Rats","volume":"118","author":"Kujal","year":"2014","journal-title":"Life Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"F1448","DOI":"10.1152\/ajprenal.00340.2009","article-title":"Unlike Each Drug Alone, Lisinopril If Combined with Avosentan Promotes Regression of Renal Lesions in Experimental Diabetes","volume":"297","author":"Gagliardini","year":"2009","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_86","first-page":"gfac067.060","article-title":"Sparsentan, the Dual Endothelin Angiotensin Receptor Antagonist (Deara), Attenuates Albuminuria and Protects from the Development of Renal Injury to a Greater Extent Than Losartan in the Gddy Mouse Model of Iga Nephropathy: A 16-Week Study","volume":"37","author":"Nagasawa","year":"2022","journal-title":"ERA Congr."},{"key":"ref_87","first-page":"gfac067.054","article-title":"Sparsentan Protects the Glomerular Basement Membrane and Glycocalyx, and Attenuates Proteinuria in a Rat Model of Focal Segmental Glomerulosclerosis (FSGS)","volume":"37","author":"Bedard","year":"2022","journal-title":"ERA Congr."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Gyarmati, G., Deepak, S.K., Shroff, U.N., Izuhara, A., Komers, R., Bedard, P.W., and Peti-Peterdi, J. (2022, January 3\u20136). Sparsentan Improves Glomerular Endothelial and Podocyte Functions and Augments Protective Tissue Repair in a Mouse Model of Focal Segmental Glomerulosclerosis (FSGS). Proceedings of the American Society of Nephrology (ASN) Kidney Week 2022\u2014Session: Glomerular Diseases: From Bench to Bedside, Orlando, FL, USA.","DOI":"10.1681\/ASN.20223311S133a"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1139\/cjpp-2022-0082","article-title":"Lack of Renoprotective Effects of Targeting the Endothelin A Receptor and (or) Sodium Glucose Transporter 2 in a Mouse Model of Type 2 Diabetic Kidney Disease","volume":"100","author":"Stuart","year":"2022","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Vergara, A., Jacobs-Cacha, C., Llorens-Cebria, C., Ortiz, A., Martinez-Diaz, I., Martos, N., Dominguez-B\u00e1ez, P., Van den Bosch, M.M., Bermejo, S., and Pieper, M.P. (2022). Enhanced Cardiorenal Protective Effects of Combining SGLT2 Inhibition, Endothelin Receptor Antagonism and RAS Blockade in Type 2 Diabetic Mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112823"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1016\/S0140-6736(09)61500-2","article-title":"A Selective Endothelin-Receptor Antagonist to Reduce Blood Pressure in Patients with Treatment-Resistant Hypertension: A Randomised, Double-Blind, Placebo-Controlled Trial","volume":"374","author":"Weber","year":"2009","journal-title":"Lancet"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1681\/ASN.2010080869","article-title":"Addition of Atrasentan to Renin-Angiotensin System Blockade Reduces Albuminuria in Diabetic Nephropathy","volume":"22","author":"Kohan","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1161\/HYPERTENSIONAHA.110.167486","article-title":"Selective Endothelin-a Receptor Antagonism Reduces Proteinuria, Blood Pressure, and Arterial Stiffness in Chronic Proteinuric Kidney Disease","volume":"57","author":"Dhaun","year":"2011","journal-title":"Hypertension"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1161\/CIRCULATIONAHA.120.045691","article-title":"Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects","volume":"142","author":"Griffin","year":"2020","journal-title":"Circulation"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/S2213-8587(20)30300-4","article-title":"Effects of Canagliflozin on Anaemia in Patients with Type 2 Diabetes and Chronic Kidney Disease: A Post-Hoc Analysis from the CREDENCE Trial","volume":"8","author":"Oshima","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.kint.2020.09.026","article-title":"New Insights from SONAR Indicate Adding Sodium Glucose Co-Transporter 2 Inhibitors to an Endothelin Receptor Antagonist Mitigates Fluid Retention and Enhances Albuminuria Reduction","volume":"99","author":"Heerspink","year":"2021","journal-title":"Kidney Int."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1681\/ASN.2018010091","article-title":"DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS","volume":"29","author":"Trachtman","year":"2018","journal-title":"J. Am. Soc. Nephrol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3427\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:28:39Z","timestamp":1760120919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3427"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,8]]},"references-count":97,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043427"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043427","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,8]]}}}