Enhanced Cardiorenal Protective Effects of Combining SGLT2 Inhibition, Endothelin Receptor Antagonism and RAS Blockade in Type 2 Diabetic Mice
Vergara, Ander (Hospital Universitari Vall d'Hebron)
Jacobs-Cachá, Conxita (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Llorens-Cebria, Carmen (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ortiz, Alberto (Universidad Autónoma de Madrid)
Martinez-Diaz, Irene (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Martos, Nerea (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Dominguez-Báez, Pamela (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Van den Bosch, Mireia Molina (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Bermejo García, Sheila (Hospital Universitari Vall d'Hebron)
Pieper, Michael Paul (Boehringer Ingelheim Pharma GmbH (Alemanya))
Benito, Begoña (Universitat Autònoma de Barcelona. Departament de Medicina)
Soler, Maria Jose (Hospital Universitari Vall d'Hebron)

Date:	2022
Abstract:	Treatments with sodium-glucose 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-angiotensin 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.
Grants:	Instituto de Salud Carlos III PI17/00257 Instituto de Salud Carlos III RD21/0005/0016
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Diabetes ; Diabetic nephropathy ; Chronic kidney disease ; Sodium-glucose cotransporter 2 inhibitors ; Endothelin receptor antagonists
Published in:	International journal of molecular sciences, Vol. 23 (october 2022) , ISSN 1422-0067

DOI: 10.3390/ijms232112823
PMID: 36361612

23 p, 3.3 MB

The record appears in these collections:
Articles > Research articles
Articles > Published articles