Vasopeptidase inhibition prevents nephropathy in Zucker diabetic fatty rats.
BACKGROUND
Blocking the renin-angiotensin system is an established therapeutic principle in diabetic nephropathy. We investigated whether inhibition of both neutral endopeptidase and ACE (vasopeptidase inhibition) can prevent functional and morphological features of nephropathy in the Zucker diabetic fatty (ZDF) rat, an animal model of type II diabetes.


METHODS
Homozygous (fa/fa) ZDF rats (each n=15) aged 10 weeks were treated with placebo, ramipril (1 mg/kg/day in drinking water), or the vasopeptidase inhibitor AVE7688 (45 mg/kg/day in chow). Metabolic parameters and renal function (metabolic cages) were assessed at baseline (age 10 weeks), and at age 17, 27, and 37 weeks. Twenty heterozygous animals (fa/-) served as lean, nondiabetic controls. At age 37 weeks, the animals were sacrificed and the kidneys analyzed histopathologically.


RESULTS
Overt diabetes mellitus (blood glucose >20 mmol/l) was established at age 17 weeks in all homozygous ZDF rats. In the placebo group, urinary protein excretion increased progressively from 8+/-1 (baseline) to 342+/-56 mg/kg/day (week 37) whereas diabetes and proteinuria were absent in the lean control group. Ramipril tended to reduce albuminuria and morphological damage (p=ns) but AVE7688 virtually prevented albuminuria (33+/-12 mg/kg/day, p<0.05 vs. ZDF placebo) and drastically reduced the incidence and severity of glomerulosclerosis and tubulointerstitial damage.


CONCLUSIONS
In ZDF rats, development of diabetes mellitus is accompanied by functional and morphological kidney damage that resembles human diabetic nephropathy. Diabetic nephropathy can be prevented by chronic vasopeptidase inhibition.
Schäfer
Stefan
S
Disease Group Cardiovascular Diseases, Aventis Pharma Deutschland GmbH, Building H 821, D-65926, Frankfurt am Main, Germany. stefan.schafer@aventis.com
Linz
Wolfgang
W
Bube
Axel
A
Gerl
Martin
M
Huber
Jochen
J
Kürzel
Gert Ulrich
GU
Bleich
Markus
M
Schmidts
Hans-Ludwig
HL
Busch
Andreas E
AE
Rütten
Hartmut
H
D000419:Albuminuria / Q000188:drug therapy; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D019540:Area Under Curve; D001552:Benzazepines / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006207:Half-Life; D006575:Heterocyclic Compounds, 3-Ring / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011355:Prodrugs; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000097:blood; D017257:Ramipril / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker
C481391:7-((2-(acetylthio)-1-oxo-3-methylpropyl)amino)-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido(2,1-a)(2)benzazepin-4-carboxyacid; C479877:AVE 7688; D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D011355:Prodrugs; D011480:Protease Inhibitors; D011725:Pyridines; D007703:Peptidyl-Dipeptidase A; D017257:Ramipril