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Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progressi...

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Autores principales: Beraldo, Juliana Isa, Benetti, Acaris, Borges-Júnior, Flávio Araújo, Arruda-Junior, Daniel F., Martins, Flavia Letícia, Jensen, Leonardo, Dariolli, Rafael, Shimizu, Maria Heloisa, Seguro, Antonio C., Luchi, Weverton M., Girardi, Adriana C. C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515057/
https://www.ncbi.nlm.nih.gov/pubmed/31010001
http://dx.doi.org/10.3390/ijms20081940
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author Beraldo, Juliana Isa
Benetti, Acaris
Borges-Júnior, Flávio Araújo
Arruda-Junior, Daniel F.
Martins, Flavia Letícia
Jensen, Leonardo
Dariolli, Rafael
Shimizu, Maria Heloisa
Seguro, Antonio C.
Luchi, Weverton M.
Girardi, Adriana C. C.
author_facet Beraldo, Juliana Isa
Benetti, Acaris
Borges-Júnior, Flávio Araújo
Arruda-Junior, Daniel F.
Martins, Flavia Letícia
Jensen, Leonardo
Dariolli, Rafael
Shimizu, Maria Heloisa
Seguro, Antonio C.
Luchi, Weverton M.
Girardi, Adriana C. C.
author_sort Beraldo, Juliana Isa
collection PubMed
description Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.
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spelling pubmed-65150572019-05-30 Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease Beraldo, Juliana Isa Benetti, Acaris Borges-Júnior, Flávio Araújo Arruda-Junior, Daniel F. Martins, Flavia Letícia Jensen, Leonardo Dariolli, Rafael Shimizu, Maria Heloisa Seguro, Antonio C. Luchi, Weverton M. Girardi, Adriana C. C. Int J Mol Sci Article Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes. MDPI 2019-04-20 /pmc/articles/PMC6515057/ /pubmed/31010001 http://dx.doi.org/10.3390/ijms20081940 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Beraldo, Juliana Isa
Benetti, Acaris
Borges-Júnior, Flávio Araújo
Arruda-Junior, Daniel F.
Martins, Flavia Letícia
Jensen, Leonardo
Dariolli, Rafael
Shimizu, Maria Heloisa
Seguro, Antonio C.
Luchi, Weverton M.
Girardi, Adriana C. C.
Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease
title Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease
title_full Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease
title_fullStr Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease
title_full_unstemmed Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease
title_short Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease
title_sort cardioprotection conferred by sitagliptin is associated with reduced cardiac angiotensin ii/angiotensin-(1-7) balance in experimental chronic kidney disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515057/
https://www.ncbi.nlm.nih.gov/pubmed/31010001
http://dx.doi.org/10.3390/ijms20081940
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