Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat.
OBJECTIVE
Diabetic renal disease has been postulated to progress as a result of an interaction between metabolic and haemodynamic pathways. Our aim was to assess the functional, structural, molecular and cellular aspects of renal disease in an experimental model of diabetes with associated hypertension.


METHODS
Streptozotocin-induced diabetic spontaneously hypertensive rats were randomised to no treatment, the ACE inhibitor, perindopril (2 mg/l), the AGE formation inhibitor, aminoguanidine (1 g/l) and a combination of both agents and were followed for 32 weeks.


RESULTS
Diabetes was associated with a considerable increase in albumin excretion rate. Both aminoguanidine and perindopril retarded the increase in albuminuria, which was completely abrogated by combination therapy. Glomerulosclerosis and tubulointerstitial damage was reduced by both monotherapies with further renoprotection afforded by combination therapy in both cases. Combination therapy was also associated with a superior restoration in diabetes-induced nephrin protein depletion compared to either monotherapy. TGFbeta1 expression as assessed by in situ hybridisation was increased in the diabetic rats and reduced by perindopril and aminoguanidine.


CONCLUSIONS
These findings indicate that in the context of diabetes-related renal injury, blocking both the renin-angiotensin and advanced glycation pathways offers superior renoprotection and could be considered as a therapeutic strategy in the prevention and retardation of progressive-diabetic renal injury.
Davis
B J
BJ
Diabetic Complications Group, Baker Heart Research Institute, P.O. Box 6492, Prahran, Melbourne, Victoria 8008, Australia. belinda.davis@baker.edu.au
Forbes
J M
JM
Thomas
M C
MC
Jerums
G
G
Burns
W C
WC
Kawachi
H
H
Allen
T J
TJ
Cooper
M E
ME
D000419:Albuminuria; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000652:urine*; D003928:Diabetic Nephropathies / Q000517:prevention & control* / Q000652:urine; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006146:Guanidines / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D020913:Perindopril / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006146:Guanidines; C004479:pimagedine; D020913:Perindopril