Effect of antioxidants and ACE
inhibition on chemical modification of proteins and progression of
nephropathy in the streptozotocin diabetic rat.
Alderson NL, Chachich ME, Frizzell N,
Canning P, Metz TO,
Januszewski AS, Youssef NN, Stitt AW, Baynes JW,
Thorpe SR.
Department of Chemistry and Biochemistry
University of South Carolina,
Columbia, South Carolina, USA.
Diabetologia. 2004 Aug;47(8):1385-95.
Abstract
AIMS/HYPOTHESIS. 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)) ~ 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/INTERPRETATION. 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.
