title: Activation of the GLP-1 Receptor by Liraglutide Increases ACE2 Expression, Reversing Right Ventricle Hypertrophy, and Improving the Production of SP-A and SP-B in the Lungs of Type 1 Diabetes Rats.
abstract: Diabetes alters microvascular function in the vascular beds of organs, including the lungs. Cardiovascular complications of pulmonary vascular affectation may be a consequence of the overactivation of the vasoconstrictive and proliferative components of the renin-angiotensin system. We previously reported that pulmonary physiology and surfactant production is improved by the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide (LIR) in a rat model of lung hypoplasia. Because we hypothesized that streptozotocin-induced diabetes rats would show deficiencies in lung function, including surfactant proteins, and develop an imbalance of the renin-angiotensin system in the lungs. This effect would in turn be prevented by long-acting agonists of the GLP-1R, such as LIR. The induction of diabetes reduced the surfactant protein A and B in the lungs and caused the vasoconstrictor component of the renin-angiotensin system to predominate, which in turn increased angiotensin II levels, and ultimately being associated with right ventricle hypertrophy. LIR restored surfactant protein levels and reversed the imbalance in the renin-angiotensin system in this type 1 diabetes mellitus rat model. Moreover, LIR provoked a strong increase in angiotensin-converting enzyme 2 expression in the lungs of both diabetic and control rats, and in the circulating angiotensin(1-7) in diabetic animals. These effects prompted complete reversion of right ventricle hypertrophy. The consequences of LIR administration were independent of glycemic control and of glucocorticoids, and they involved NK2 homeobox 1 signaling. This study demonstrates by first time that GLP-1R agonists, such as LIR, might improve the cardiopulmonary complications associated with diabetes.
authors.affiliation: Laboratory of Endocrinology (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), Centre for Biomedical Research (CINBIO), University of Vigo, Faculty of Biology, E-36310 Vigo, Spain; Institute for Biomedical Research of Vigo (IBIV) (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), University of Vigo/Sergas, E36310, Vigo, Spain; and Institute Biomedical Research Alberto Sols (C.M.M., P.S.), Spanish Council of Research, Universidad Autónoma de Madrid, Madrid E28029, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Romaní-Pérez
authors.affiliation: Laboratory of Endocrinology (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), Centre for Biomedical Research (CINBIO), University of Vigo, Faculty of Biology, E-36310 Vigo, Spain; Institute for Biomedical Research of Vigo (IBIV) (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), University of Vigo/Sergas, E36310, Vigo, Spain; and Institute Biomedical Research Alberto Sols (C.M.M., P.S.), Spanish Council of Research, Universidad Autónoma de Madrid, Madrid E28029, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Outeiriño-Iglesias
authors.affiliation: Laboratory of Endocrinology (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), Centre for Biomedical Research (CINBIO), University of Vigo, Faculty of Biology, E-36310 Vigo, Spain; Institute for Biomedical Research of Vigo (IBIV) (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), University of Vigo/Sergas, E36310, Vigo, Spain; and Institute Biomedical Research Alberto Sols (C.M.M., P.S.), Spanish Council of Research, Universidad Autónoma de Madrid, Madrid E28029, Spain.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Moya
authors.affiliation: Laboratory of Endocrinology (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), Centre for Biomedical Research (CINBIO), University of Vigo, Faculty of Biology, E-36310 Vigo, Spain; Institute for Biomedical Research of Vigo (IBIV) (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), University of Vigo/Sergas, E36310, Vigo, Spain; and Institute Biomedical Research Alberto Sols (C.M.M., P.S.), Spanish Council of Research, Universidad Autónoma de Madrid, Madrid E28029, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Santisteban
authors.affiliation: Laboratory of Endocrinology (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), Centre for Biomedical Research (CINBIO), University of Vigo, Faculty of Biology, E-36310 Vigo, Spain; Institute for Biomedical Research of Vigo (IBIV) (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), University of Vigo/Sergas, E36310, Vigo, Spain; and Institute Biomedical Research Alberto Sols (C.M.M., P.S.), Spanish Council of Research, Universidad Autónoma de Madrid, Madrid E28029, Spain.
authors.forename: Lucas C
authors.initials: LC
authors.lastname: González-Matías
authors.affiliation: Laboratory of Endocrinology (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), Centre for Biomedical Research (CINBIO), University of Vigo, Faculty of Biology, E-36310 Vigo, Spain; Institute for Biomedical Research of Vigo (IBIV) (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), University of Vigo/Sergas, E36310, Vigo, Spain; and Institute Biomedical Research Alberto Sols (C.M.M., P.S.), Spanish Council of Research, Universidad Autónoma de Madrid, Madrid E28029, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Vigo
authors.affiliation: Laboratory of Endocrinology (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), Centre for Biomedical Research (CINBIO), University of Vigo, Faculty of Biology, E-36310 Vigo, Spain; Institute for Biomedical Research of Vigo (IBIV) (M.R.-P., V.O.-I., L.C.G.-M., E.V., F.M.), University of Vigo/Sergas, E36310, Vigo, Spain; and Institute Biomedical Research Alberto Sols (C.M.M., P.S.), Spanish Council of Research, Universidad Autónoma de Madrid, Madrid E28029, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Mallo
mesh_terms: D000792:Angiography; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000069450:Liraglutide / Q000627:therapeutic use*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D037662:Pulmonary Surfactant-Associated Protein A / Q000378:metabolism*; D037701:Pulmonary Surfactant-Associated Protein B / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D037662:Pulmonary Surfactant-Associated Protein A; D037701:Pulmonary Surfactant-Associated Protein B; D013501:Surface-Active Agents; D000069450:Liraglutide; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2