Abstract
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.
Original language | English (US) |
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Pages (from-to) | 939-950 |
Number of pages | 12 |
Journal | Kidney international |
Volume | 61 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2002 |
Bibliographical note
Funding Information:This work was supported by research grants from BioStratum, Inc., and from the National Institute of Diabetes, Digestive, and Kidney Disease [DK-19971 (JWB) and DK-43605 (MWS)]. The authors gratefully acknowledge the expert technical assistance of Ms. Margaret Rentz and Ms. Pamela Rudd in the University of South Carolina Animal Resources Facility. We also thank Dr. Billy G. Hudson and Dr. Raja Khalifah, Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, MO, for helpful discussions and suggestions. T.P.D. is currently employed by BioStratum, Inc. J.W.B. is a member of the Scientific Advisory Board of BioStratum, Inc.
Keywords
- Advanced glycation end-product
- Advanced lipoxidation end-product
- Albuminuria
- Aminoguanidine
- Collagen
- Dyslipidemia
- Hyperglycemia
- N-(carboxymethyl)lysine (CML)