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Int J Mol Sci. 2019 Apr 20;20(8). pii: E1940. doi: 10.3390/ijms20081940.

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

Author information

1
Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-900, SP, Brazil. juliana_isab@hotmail.com.
2
Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-900, SP, Brazil. acaris.ben@gmail.com.
3
Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-900, SP, Brazil. flavio44jr@gmail.com.
4
Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-900, SP, Brazil. danielarruda.junior@gmail.com.
5
Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-900, SP, Brazil. flaviabiomack@gmail.com.
6
Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-900, SP, Brazil. jensenleonardo@gmail.com.
7
Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-900, SP, Brazil. rdariolli@gmail.com.
8
Department of Nephrology (LIM 12), University of São Paulo Medical School, São Paulo 05403-900, SP, Brazil. hmshimizu@gmail.com.
9
Department of Nephrology (LIM 12), University of São Paulo Medical School, São Paulo 05403-900, SP, Brazil. trulu@usp.br.
10
Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-900, SP, Brazil. wmluchi@hotmail.com.
11
Department of Internal Medicine, Federal University of Espírito Santo (UFES), Vitoria 29040-090, Espírito Santo, Brazil. wmluchi@hotmail.com.
12
Heart Institute (InCor), University of São Paulo Medical School, São Paulo 05403-900, SP, Brazil. adriana.girardi@incor.usp.br.

Abstract

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.

KEYWORDS:

5/6 renal ablation; cardiorenal syndromes; dipeptidyl peptidase IV; renin-angiotensin system

PMID:
31010001
PMCID:
PMC6515057
DOI:
10.3390/ijms20081940
[Indexed for MEDLINE]
Free PMC Article

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