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Cell Biochemistry and Biophysics

, Volume 48, Issue 2–3, pp 147–157 | Cite as

Novel inhibitors of glycation and AGE formation

  • Samuel RahbarEmail author
Original Paper

Abstract

Accelerated formation of advanced glycation/lipoxidation and endproducts (AGEs/ALEs) has been implicated in the pathogenesis of various diabetic complications. Several natural and synthetic compounds have been proposed and tested as inhibitors of AGE/ALE formation. We have previously reported the therapeutic effects of several new AGE/ALE inhibitors on the prevention of nephropathy and dyslipidemia in streptozotocin (STZ)-induced diabetic rats. In this study, we investigated the effects of various concentrations of a compound, LR-90, on the progression of renal disease and its effects on AGE and receptor for AGE (RAGE) protein expression on the kidneys of diabetic STZ-rats. Diabetic male Sprague–Dawley rats were treated with or without LR-90 (0, 5, 20, 25, and 50 mg/l of drinking water). After 32 weeks, body weight, glycemic status, renal function, and plasma lipids were measured. Kidney histopathology and AGE/ALE accumulation and RAGE protein expression in tissues were also determined. In vitro studies were also performed to determine the possible mechanism of action of LR-90 in inhibiting AGE formation and AGE-protein cross-linking. LR-90 protected the diabetic kidneys by inhibiting the increase in urinary albumin-to-creatinine ratio and ameliorated hyperlipidemia in diabetic rats in a concentration-dependent fashion without any effects on hyperglycemia. LR-90 treatment also reduced kidney AGE/ALE accumulation and RAGE protein expression in a concentration-dependent manner. In vitro, LR-90 exhibited general antioxidant properties by inhibiting metal-catalyzed reactions and reactive oxygen species (·OH radical) and reactive carbonyl species (methlyglyoxal, glyoxal) generations without any effect on pyridoxal 5′ phosphate. The compound also prevents AGE-protein cross-linking reactions. These findings demonstrate the bioefficacy of LR-90 in treating nephropathy and hyperlipidemia in diabetic animals by inhibiting AGE accumulation, RAGE protein expression, and protein oxidation in the diabetic kidney. Additionally, our study suggests that LR-90 may be useful also to delay the onset and progression of diabetic atherosclerosis as the compound can inhibit the expression of RAGE and inflammation-related pathology, as well as prevent lipid peroxidation reactions.

Keywords

Glycation Lipoxidation Diabetes Nephropathy Oxidative stress Dyslipidemia 

Abbreviations

ACR

Albumin-to-creatinine ratio

AGEs

Advanced glycation endproducts

ALEs

Advanced lipoxidation endproducts

CML

Nε-(carboxymethyl)lysine

LDL

Low density lipoprotein

RAGE

Receptor for advanced glycation endproducts

RCS

Reactive carbonyl species

ROS

Reactive oxygen species

TBARS

Thiobarbituric acid reactive substances

Notes

Acknowledgment

The author would like to thank Ms. Autumn Tate for her secretarial assistance.

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Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Department of Diabetes, Endocrinology and Metabolism, Beckman Research InstituteCity of Hope National Medical CenterDuarteUSA

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