Abstract
BackgroundDipeptidyl peptidase 4 (DPP4) and angiotensin-converting enzyme (ACE) are important target enzymes in glycemic control and renovascular protection. Here, we studied the effect of NWT-03, an egg protein hydrolysate with DPP4- and ACE-inhibitory activity, on renovascular damage in Zucker diabetic fatty (ZDF) rats. Comparisons were made to rats treated with vildagliptin (VIL), included as a positive control for the effect of DPP4 inhibition.MethodsZDF rats received NWT-03 (1 g/kg/day) or VIL (3 mg/kg/day) from 10 to 25 weeks of age. Metabolic and renal functions were assessed; the kidney was removed for histological analysis of glomerulosclerosis and expression of pro-inflammatory/fibrotic markers (RT-PCR and Western blotting); and the aorta was removed for studies of endothelium-dependent relaxation (EDR).FindingsHyperinsulinemic ZDF rats typically developed signs of type-2 diabetes and renovascular damage, as evidenced by albuminuria, glomerulosclerosis, and impaired EDR. Neither NWT-03 nor VIL improved metabolic parameters; for VIL, this was despite a 5-fold increase in glucagon-like peptide (GLP)-1 levels. NWT-03 and VIL both reduced renal interleukin (Il)-1β/Il-13 mRNA expression and glomerulosclerosis. However, only NWT-03 additionally decreased renal tumor necrosis factor (TNF)-α mRNA and P22phox protein expression, reduced albuminuria, and restored aortic EDR. Indomethacin added to the organ bath instantly improved aortic EDR, indicating a role for cyclooxygenase (COX)-derived contractile prostanoids in opposing relaxation in ZDF rats. This indomethacin effect was reduced by NWT-03, but not by VIL, and coincided with decreased renal COX-1/2 protein expression.Conclusion and InterpretationLong-term supplementation with the egg protein hydrolysate NWT-03 attenuated renovascular damage in this preclinical rat model of type 2 diabetes. A comparison to the DPP4-inhibitor VIL suggests that the effects of NWT-03 were related to both ACE- and DPP4-inhibitory properties. The development of protein hydrolysates with a multiple-targeting strategy may be of benefit to functional food formulations.
Highlights
Food-derived bioactive peptides represent a source of healthenhancing components that may be incorporated in functional foods
A comparison to the Dipeptidyl peptidase 4 (DPP4)-inhibitor VIL suggests that the effects of NWT-03 were related to both angiotensin-converting enzyme (ACE)- and DPP4-inhibitory properties
The development of protein hydrolysates with a multiple-targeting strategy may be of benefit to functional food formulations
Summary
Food-derived bioactive peptides represent a source of healthenhancing components that may be incorporated in functional foods. Quantitative in silico analyses may be used to calculate bioactivity in protein digests and identify good potential sources of peptides of interest [2,3] In such a search, we identified the egg protein lysozyme as a potential precursor protein of angiotensin-converting enzyme (ACE)-inhibitory peptides upon digestion with alcalase. We identified the egg protein lysozyme as a potential precursor protein of angiotensin-converting enzyme (ACE)-inhibitory peptides upon digestion with alcalase The activity of this hydrolysate, termed NWT-03, was confirmed in subsequent in vitro ACE-inhibition assays (IC50 = 0.07 mg/mL) (Buikema et al, unpublished data). ACEinhibitors have emerged as important agents, in the management of hypertension and for their potential to reduce cardiovascular risk and nephropathy; they provide renovascular protection through different mechanisms beyond their primary therapeutic actions [4,5]. Comparisons were made to rats treated with vildagliptin (VIL), included as a positive control for the effect of DPP4 inhibition
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