Effects of DPP-4 inhibitors on the heart in a rat model of uremic cardiomyopathy

Abstract

Background: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4).

Methodology/principal findings: In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-∞) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞) values; 41% and 28% (p = 0.0001 and p = 0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p = 0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin.

Conclusions/significance: DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.

Figure 1. Experimental design.

Figure 2. mRNA expression of BNP in uremic rat heart.

Gene expression of the marker of left ventricular dysfunction BNP was significantly increased in rats after initiation of uremia. Treatment with linagliptin at a dose of 7 µmol/kg significantly reduced mRNA expression of BNP in uremic rat heart. Values are given in mean ± SEM. N = 7 sham-operated rats, 5 5/6N rats and 12 5/6N linagliptin-treated rats. *p<0.05; ***p<0.001.

Figure 3. Gene expression of fibrosis markers in uremic rat heart.

Uremic condition led to a significant increase in gene expression of profibrotic factors TGF-β1, TIMP-1, Col1α1 and Col3α1 in the 5/6 nephrectomized rats compared with corresponding sham-operated rats. Linagliptin at a dose of 7 µmol/kg significantly inhibited mRNA expression of profibrotic factors TGF-β1, TIMP-1, Col1α1 and Col3α1 in uremic rat heart. Values are given in mean ± SEM. N = 7 sham-operated rats, 5 5/6N rats, and 12 5/6N linagliptin-treated rats. *p<0.05; ***p<0.001.

Figure 4. Influence of DPP-4 inhibition on cardiac impairment in the setting of uremia.

Figure 5. Active GLP-1 levels in uremic vs sham animals.

The uremic situation resulted in a significant increase of GLP-1 AUC in 5/6N rats compared with controls. Linagliptin (7 µmol/kg) was administered daily for 4 days. Following the last dose, plasma was taken after the time points indicated and active GLP-1 was detected. Values are given as mean ± SEM. N = 5 sham-operated, and 8-12 rats for 5/6N.