Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat.
BACKGROUND
Nonenzymatic reactions between sugars or lipids and protein and formation of advanced glycation and lipoxidation end products (AGE/ALEs) contribute to the chemical modification and cross-linking of tissue proteins with age. Accelerated formation of AGE/ALEs during hyperglycemia is implicated in the development of diabetic complications. In this study, we examined the effect of the AGE/ALE inhibitor pyridoxamine on chemical modification and cross-linking of collagen and development of renal disease in the streptozotocin-diabetic rat.


METHODS
Diabetic rats were treated with pyridoxamine; parallel experiments were conducted with aminoguanidine, the prototype AGE inhibitor. Progression of renal disease was evaluated by measurements of albuminuria and plasma creatinine concentration. Plasma triglycerides, cholesterol, lactate and pyruvate were measured by enzymatic assays, and AGE/ALEs in skin collagen by HPLC and GC-MS assays.


RESULTS
Pyridoxamine significantly inhibited the increase in albuminuria, plasma creatinine, hyperlipidemia and plasma lactate/pyruvate ratio in diabetic rats, without an effect on blood glucose or glycated hemoglobin. AGE/ALEs, fluorescence and cross-linking of skin collagen increased approximately twofold in diabetic versus control rats after seven months of diabetes. Pyridoxamine caused a significant (25 to 50%) decrease the AGE/ALEs, carboxymethyllysine and carboxyethyllysine, cross-linking and fluorescence in skin collagen of diabetic rats, but did not affect pentosidine.


CONCLUSIONS
Pyridoxamine inhibits the progression of renal disease, and decreases hyperlipidemia and apparent redox imbalances in diabetic rats. Pyridoxamine and aminoguanidine had similar effects on parameters measured, supporting a mechanism of action involving AGE/ALE inhibition.
Degenhardt
Thorsten P
TP
Department of Chemistry, Animal Resource Facility, University of South Carolina, Columbia, SC 29208, USA.
Alderson
Nathan L
NL
Arrington
David D
DD
Beattie
Robert J
RJ
Basgen
John M
JM
Steffes
Michael W
MW
Thorpe
Suzanne R
SR
Baynes
John W
JW
D000818:Animals; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018450:Disease Progression; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006146:Guanidines / Q000097:blood / Q000652:urine; D006949:Hyperlipidemias / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D050356:Lipid Metabolism; D010084:Oxidation-Reduction; D011733:Pyridoxamine / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
D017127:Glycation End Products, Advanced; D006146:Guanidines; D011733:Pyridoxamine; D003094:Collagen; C004479:pimagedine