{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:40:32Z","timestamp":1790404832847,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T00:00:00Z","timestamp":1666569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"FONDO DE INVESTIGACI\u00d3N SANITARIA-FEDER, ISCIII","doi-asserted-by":"publisher","award":["PI17\/00257"],"award-info":[{"award-number":["PI17\/00257"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"FONDO DE INVESTIGACI\u00d3N SANITARIA-FEDER, ISCIII","doi-asserted-by":"publisher","award":["RICORS RD21\/0005\/0016"],"award-info":[{"award-number":["RICORS RD21\/0005\/0016"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Boehringer Ingelheim Pharma GmbH","award":["PI17\/00257"],"award-info":[{"award-number":["PI17\/00257"]}]},{"name":"Boehringer Ingelheim Pharma GmbH","award":["RICORS RD21\/0005\/0016"],"award-info":[{"award-number":["RICORS RD21\/0005\/0016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Treatments with sodium\u2013glucose 2 cotransporter inhibitors (SGLT2i) or endothelin receptor antagonists (ERA) have shown cardiorenal protective effects. The present study aimed to evaluate the cardiorenal beneficial effects of the combination of SGLT2i and ERA on top of renin\u2013angiotensin system (RAS) blockade. Type 2 diabetic mice (db\/db) were treated with different combinations of an SGLT2i (empagliflozin), an ERA (atrasentan), and an angiotensin-converting enzyme inhibitor (ramipril) for 8 weeks. Vehicle-treated diabetic mice and non-diabetic mice were included as controls. Weight, blood glucose, blood pressure, and kidney and heart function were monitored during the study. Kidneys and heart were collected for histological examination and to study the intrarenal RAS. Treatment with empagliflozin alone or combined significantly decreased blood glucose compared to vehicle-treated db\/db. The dual and triple therapies achieved significantly greater reductions in diastolic blood pressure than ramipril alone. Compared to vehicle-treated db\/db, empagliflozin combined with ramipril or in triple therapy significantly prevented GFR increase, but only the triple combination exerted greater protection against podocyte loss. In the heart, empagliflozin alone or combined reduced cardiac isovolumetric relaxation time (IVRT) and left atrium (LA) diameter as compared to vehicle-treated db\/db. However, only the triple therapy was able to reduce cardiomyocyte area. Importantly, the add-on triple therapy further enhanced the intrarenal ACE2\/Ang(1-7)\/Mas protective arm of the RAS. These data suggest that triple therapy with empagliflozin, atrasentan and ramipril show synergistic cardiorenal protective effects in a type 2 diabetic mouse model.<\/jats:p>","DOI":"10.3390\/ijms232112823","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T10:09:23Z","timestamp":1666606163000},"page":"12823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Enhanced Cardiorenal Protective Effects of Combining SGLT2 Inhibition, Endothelin Receptor Antagonism and RAS Blockade in Type 2 Diabetic Mice"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1926-0147","authenticated-orcid":false,"given":"Ander","family":"Vergara","sequence":"first","affiliation":[{"name":"Nephrology and Kidney Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"},{"name":"Nephrology Department, Vall d\u2019Hebron Hospital Universitari, 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-Cacha","sequence":"additional","affiliation":[{"name":"Nephrology and Kidney Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), 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-Cebria","sequence":"additional","affiliation":[{"name":"Nephrology and Kidney Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9805-9523","authenticated-orcid":false,"given":"Alberto","family":"Ortiz","sequence":"additional","affiliation":[{"name":"IIS-Fundaci\u00f3n Jim\u00e9nez Diaz, Fundaci\u00f3n Renal I\u00f1igo \u00c1lvarez de Toledo-IRSIN, REDinREN, Instituto de Investigaci\u00f3n Carlos III, Universidad Aut\u00f3noma de Madrid, Av. de los Reyes Cat\u00f3licos 2, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5849-7900","authenticated-orcid":false,"given":"Irene","family":"Martinez-Diaz","sequence":"additional","affiliation":[{"name":"Nephrology and Kidney Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerea","family":"Martos","sequence":"additional","affiliation":[{"name":"Nephrology and Kidney Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Dominguez-B\u00e1ez","sequence":"additional","affiliation":[{"name":"Nephrology and Kidney Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireia Molina","family":"Van den Bosch","sequence":"additional","affiliation":[{"name":"Nephrology and Kidney Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3611-4830","authenticated-orcid":false,"given":"Sheila","family":"Bermejo","sequence":"additional","affiliation":[{"name":"Nephrology and Kidney Transplantation Research Group, Vall d\u2019Hebron Institut de Recerca (VHIR), Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"},{"name":"Nephrology Department, Vall d\u2019Hebron Hospital Universitari, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Paul","family":"Pieper","sequence":"additional","affiliation":[{"name":"Cardio-Metabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. 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