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PMID: 14647892 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat.

Diabetologia ·Vol. 47 ·No. 1 ·2004-01-00 ·Pages 89-97

Davis BJ, Forbes JM, Thomas MC, Jerums G, Burns WC, Kawachi H, Allen TJ, Cooper ME

Abstract

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. 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. 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. 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.

MeSH Terms
Albuminuria Angiotensin-Converting Enzyme Inhibitors/therapeutic use Animals Diabetes Mellitus, Experimental/urine Diabetic Nephropathies/prevention & control,urine Disease Models, Animal Drug Therapy, Combination Enzyme Inhibitors/therapeutic use Guanidines/therapeutic use Kidney/drug effects,pathology,physiopathology Kidney Glomerulus/pathology Male Perindopril/therapeutic use Rats Rats, Inbred SHR
Chemicals
Angiotensin-Converting Enzyme Inhibitors Enzyme Inhibitors Guanidines pimagedine Perindopril
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Davis B J
Diabetic Complications Group, Baker Heart Research Institute, P.O. Box 6492, Prahran, Melbourne, Victoria 8008, Australia. belinda.davis@baker.edu.au
Forbes J M
Thomas M C
Jerums G
Burns W C
Kawachi H
Allen T J
Cooper M E
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Article Info
Journal
Diabetologia
Abbr.
Diabetologia
ISSN
0012-186X
DOI
10.1007/s00125-003-1256-8
Email
belinda.davis@baker.edu.au
Published
2004-01-00
Epub
2003-00-29
Pages
89-97
Language
English
Region
Germany
NLM ID
0006777
Subset
IM
Corrections
CommentIn
PMID: 15278280
External Links
PubMed source DOI: 10.1007/s00125-003-1256-8 View journal details
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