Attenuation of renovascular damage in Zucker diabetic fatty rat by NWT-03, an egg protein hydrolysate with ACE- and DPP4-inhibitory Activity.
BACKGROUND
Dipeptidyl 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.


METHODS
ZDF 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).


RESULTS
Hyperinsulinemic 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 P22(phox) 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.


CONCLUSIONS
Long-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.
5th Medical Department, Section of Endocrinology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
Yumei
Y
Wang
Sjoerd
S
Landheer
Wiek H
WH
van Gilst
Aart
A
van Amerongen
Hans-Peter
HP
Hammes
Robert H
RH
Henning
Leo E
LE
Deelman
Hendrik
H
Buikema
D000109:Acetylcholine / Q000494:pharmacology; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D019040:E-Selectin / Q000235:genetics; D004527:Egg Proteins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011492:Protein Hydrolysates / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D000077597:Vildagliptin
D000109:Acetylcholine; D000218:Adamantane; D000806:Angiotensin-Converting Enzyme Inhibitors; D015815:Cell Adhesion Molecules; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D019040:E-Selectin; D004527:Egg Proteins; D009570:Nitriles; D007703:Peptidyl-Dipeptidase A; D011451:Prostaglandin-Endoperoxide Synthases; D011492:Protein Hydrolysates; D011759:Pyrrolidines; D014665:Vasodilator Agents; D000077597:Vildagliptin; C110936:Havcr1 protein, rat; C579614:NWT-03