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

Davis, B. J., Forbes, J. M., Thomas, M. C., Jerums, G., Burns, W. C., Kawachi, H., Allen, T. J. and Cooper, M. E. (2004) Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat. Diabetologia, 47 1: 89-97. doi:10.1007/s00125-003-1256-8


Author Davis, B. J.
Forbes, J. M.
Thomas, M. C.
Jerums, G.
Burns, W. C.
Kawachi, H.
Allen, T. J.
Cooper, M. E.
Title Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat
Journal name Diabetologia   Check publisher's open access policy
ISSN 0012-186X
1432-0428
Publication date 2004-01
Year available 2003
Sub-type Article (original research)
DOI 10.1007/s00125-003-1256-8
Open Access Status Not yet assessed
Volume 47
Issue 1
Start page 89
End page 97
Total pages 9
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Formatted abstract
Aims/hypothesis: 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.

Method: 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. TGFβ1 expression as assessed by in situ hybridisation was increased in the diabetic rats and reduced by perindopril and aminoguanidine.

Conclusion/interpretation: 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.
Keyword AGE formation
Albuminuria
Aminoguanidine
Combination therapy
Diabetic nephropathy
Glomerulosclerosis
Renin-angiotensin system
Spontaneously hypertensive rat
Transforming growth factor beta-1
Tubulointerstitial injury
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Mater Research Institute-UQ (MRI-UQ)
 
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