Article

Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy.

University of Melbourne Department of Medicine, St. Vincent's Hospital, 41 Victoria Parade, Fitzroy, 3065 Victoria, Australia.
Journal of the American Society of Nephrology (impact factor: 9.66). 10/2001; 12(10):2098-107. pp.2098-107
Source: PubMed

ABSTRACT Profibrotic cytokines and the formation of advanced-glycation end products (AGE) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology is also an important determinant of progressive renal dysfunction in diabetic nephropathy. This study sought to investigate the expression of profibrotic growth factors and matrix deposition in the glomerulus and the tubulointerstitium and to examine the effect of blocking AGE formation in experimental diabetic nephropathy. Thirty-six male Sprague-Dawley rats were randomized into control and diabetic groups. Diabetes was induced in 24 rats by streptozotocin. Twelve diabetic rats were further randomized to receive the inhibitor of AGE formation, aminoguanidine (1 g/l drinking water). At 6 mo, experimental diabetes was associated with a three-fold increase in expression of transforming growth factor (TGF)-beta1 (P < 0.01 versus control) and five-fold increase in platelet-derived growth factor (PDGF)-B gene expression (P < 0.01 versus control) in the tubulointerstitium. In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and PDGF-B mRNA in renal tubules. Aminoguanidine attenuated not only the overexpression of TGF-beta1 and PDGF-B but also reduced type IV collagen deposition in diabetic rats (P < 0.05). TGF-beta1 and PDGF mRNA within glomeruli were also similarly increased with diabetes and attenuated with aminoguanidine. The observed beneficial effects of aminoguanidine on the tubulointerstitium in experimental diabetes suggest that AGE-mediated expression of profibrotic cytokines may contribute to tubulointerstitial injury and the pathogenesis of diabetic nephropathy.

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Keywords

advanced-glycation end products
 
AGE formation
 
AGE-mediated expression
 
Aminoguanidine attenuated
 
diabetic kidney disease
 
diabetic nephropathy
 
diabetic rats
 
diffuse increase
 
experimental diabetes
 
experimental diabetic nephropathy
 
five-fold increase
 
male Sprague-Dawley rats
 
matrix deposition
 
observed beneficial effects
 
PDGF)-B gene expression
 
platelet-derived growth factor
 
profibrotic growth factors
 
renal tubules
 
three-fold increase
 
type IV collagen deposition