Effect of antioxidants and ACE inhibition on chemical modification of proteins and progression of nephropathy in the streptozotocin diabetic rat.
OBJECTIVE
This study was designed to determine whether inhibition of formation of AGE and advanced lipoxidation end-products (ALE) is a mechanism of action common to a diverse group of therapeutic agents that limit the progress of diabetic nephropathy. We compared the effects of the ACE inhibitor enalapril, the antioxidant vitamin E, the thiol compound lipoic acid, and the AGE/ALE inhibitor pyridoxamine on the formation of AGE/ALE and protection against nephropathy in streptozotocin diabetic rats.


METHODS
Renal function and AGE/ALE formation were evaluated in rats treated with the agents listed above. Plasma was monitored monthly for triglycerides, cholesterol, creatinine and TNF-alpha, and 24-h urine samples were collected for measurement of albumin and total protein excretion. After 29 weeks, renal expression of mRNA for extracellular matrix proteins was measured, and AGE/ALE were quantified in skin and glomerular and tubular collagen.


RESULTS
Diabetic animals were both hyperglycaemic and dyslipidaemic, and showed evidence of early nephropathy (albuminuria, creatinaemia). All interventions limited the progression of nephropathy, without affecting glycaemia. The order of efficacy was: pyridoxamine (650 mg.kg(-1).day(-1)) > vitamin E (200 mg.kg(-1).day(-1)) > lipoic acid (93 mg.kg(-1).day(-1)) approximately enalapril (35 mg.kg(-1).day(-1)). Pyridoxamine also significantly inhibited AGE/ALE accumulation in tissues; effects of other agents were mixed, but the degree of renoprotection was consistent with their effects on AGE/ALE formation.


CONCLUSIONS
All interventions inhibited the progression of nephropathy at the doses studied, but the maximal benefit was achieved with pyridoxamine, which also limited dyslipidaemia and AGE/ALE formation. These experiments indicate that the more effective the renoprotection, the greater the inhibition of AGE/ALE formation. For optimal protection of renal function, it would be beneficial to select drugs whose mechanism of action includes inhibition of AGE/ALE formation.
Alderson
N L
NL
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina, USA.
Chachich
M E
ME
Frizzell
N
N
Canning
P
P
Metz
T O
TO
Januszewski
A S
AS
Youssef
N N
NN
Stitt
A W
AW
Baynes
J W
JW
Thorpe
S R
SR
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D018450:Disease Progression; D005260:Female; D005353:Fibronectins / Q000235:genetics; D007677:Kidney Function Tests; D008055:Lipids / Q000097:blood; D016133:Polymerase Chain Reaction; D011733:Pyridoxamine / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D008063:Thioctic Acid / Q000627:therapeutic use; D014810:Vitamin E / Q000627:therapeutic use
D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D001786:Blood Glucose; D017931:DNA Primers; D005353:Fibronectins; D008055:Lipids; D014810:Vitamin E; D011733:Pyridoxamine; D008063:Thioctic Acid