Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure

Abstract

Circulating dipeptidyl peptidase IV (DPPIV) activity is associated with worse cardiovascular outcomes in humans and experimental heart failure (HF) models, suggesting that DPPIV may play a role in the pathophysiology of this syndrome. Renal dysfunction is one of the key features of HF, but it remains to be determined whether DPPIV inhibitors are capable of improving cardiorenal function after the onset of HF. Therefore, the present study aimed to test the hypothesis that DPPIV inhibition by vildagliptin improves renal water and salt handling and exerts anti-proteinuric effects in rats with established HF. To this end, male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were randomly divided into two groups and treated for 4 weeks with vildagliptin (120 mg/kg/day) or vehicle by oral gavage. Echocardiography was performed before (pretreatment) and at the end of treatment (post-treatment) to evaluate cardiac function. The fractional area change (FAC) increased (34 ± 5 vs. 45 ± 3%, p < 0.05), and the isovolumic relaxation time decreased (33 ± 2 vs. 27 ± 1 ms; p < 0.05) in HF rats treated with vildagliptin (post-treatment vs. pretreatment). On the other hand, cardiac dysfunction deteriorated further in vehicle-treated HF rats. Renal function was impaired in vehicle-treated HF rats as evidenced by fluid retention, low glomerular filtration rate (GFR) and high levels of urinary protein excretion. Vildagliptin treatment restored urinary flow, GFR, urinary sodium and urinary protein excretion to sham levels. Restoration of renal function in HF rats by DPPIV inhibition was associated with increased active glucagon-like peptide-1 (GLP-1) serum concentration, reduced DPPIV activity and increased activity of protein kinase A in the renal cortex. Furthermore, the anti-proteinuric effect of vildagliptin treatment in rats with established HF was associated with upregulation of the apical proximal tubule endocytic receptor megalin and of the podocyte main slit diaphragm proteins nephrin and podocin. Collectively, these findings demonstrate that DPPIV inhibition exerts renoprotective effects and ameliorates cardiorenal function in rats with established HF. Long-term studies with DPPIV inhibitors are needed to ascertain whether these effects ultimately translate into improved clinical outcomes.

Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

“…DPP‐4 inhibitors improve endothelial dysfunction, blunt inflammation and are efficient in cardiovascular and renal protection. Inflammation takes part and promotes progression of cardiovascular and renal diseases Cellular and molecular mechanisms and pathways of anti‐inflammatory activity of clinically used DPP‐4 inhibitors in cardiovascular and renal protection include the impacts on pro‐ and anti‐inflammatory mediators, cytokines, chemokines, immune cells, cell adhesion molecules, enzymes, transcription factors, pro‐ and antiapoptotic mediators, oxidative stress markers and antioxidative enzymes, receptors.…”

“…Continued evaluation of these hypoglycemic agents in longer‐term controlled trials on efficacy and safety, as well as clinical practice, are required to assess their profiles, advantages or disadvantages among the current therapies . Apart from diabetes, it has been reported that inhibitors of DPP‐4 are efficient in cardiovascular and renal protection . Cardiovascular safety of sitagliptin, linagliptin, and alogliptin in patients was confirmed in some pooled analysis and studies, but there are others pointing out enhanced risk of heart failure in diabetic patients in long‐term therapy with DPP‐4 inhibitors, with yet unexplained clear cause–effect relationship .…”

Safety, tolerability, pharmacokinetics and pharmacodynamics of parenterally administered dutogliptin: A prospective dose‐escalating trial

“…Oral administration of 400 mg dutogliptin inhibited DPP‐IV activity by approximately 85%, but led to lower plasma concentrations compared to parenteral application. We can only speculate as to whether local tissue DPP‐IV inhibition increases with plasma concentration, which might be warranted for improved cardiomyocyte recruitment, as has been suggested by preclinical models investigating vildagliptin . However, it needs to be determined how plasma and tissue concentrations of DPP‐IV activity are related.…”

“…In preclinical models of heart failure, high dose, but not low dose, administration of DPP‐IV inhibitors protected renal and improved cardiac function . This leads to the question of whether a parenteral drug formulation providing 100% bioavailability translating into continuously high DPP‐IV inhibition is possibly required to provide modulation of the SDF‐1/CXCR4 axis including these beneficial effects on cardiac remodelling.…”

Potential Role of Dipeptidyl Peptidase IV in the Pathophysiology of Heart Failure

“…Notably, the lack of vildagliptin-induced cardioprotection in this study is most likely attributed to the low dose and frequency of administration of vildagliptin employed (once-daily vs. twice-daily dosing frequency). Indeed, we have found that chronic treatment with high (120 mg/day given twice per day) but not low-dose (20 mg/kg given once a day) vildagliptin is capable of ameliorating cardiac and renal function and reducing pulmonary congestion in rats with established HF [ 140 ].…”