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

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Autor(es):
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Beraldo, Juliana Isa [1] ; Benetti, Acaris [1] ; Borges-Junior, Flavio Araujo [1] ; Arruda-Junior, Daniel F. [1] ; Martins, Flavia Leticia [1] ; Jensen, Leonardo [1] ; Dariolli, Rafael [1] ; Shimizu, Maria Heloisa [2] ; Seguro, Antonio C. [2] ; Luchi, Weverton M. [1, 3] ; Girardi, Adriana C. C. [1]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Med Sch, Heart Inst InCor, BR-05403900 Sao Paulo, SP - Brazil
[2] Univ Sao Paulo, Med Sch, Dept Nephrol LIM 12, BR-05403900 Sao Paulo, SP - Brazil
[3] Fed Univ Espirito Santo UFES, Dept Internal Med, BR-29040090 Vitoria, ES - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 20, n. 8 APR 2 2019.
Citações Web of Science: 1
Resumo

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. (AU)

Processo FAPESP: 13/10619-8 - Dipeptidil peptidase IV como um potencial alvo para a terapia da insuficiência cardíaca
Beneficiário:Adriana Castello Costa Girardi
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 16/22140-7 - Bases moleculares da função e da disfunção tubular renal
Beneficiário:Adriana Castello Costa Girardi
Linha de fomento: Auxílio à Pesquisa - Temático