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Novel inhibitors of glycation and AGE formation

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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.

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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

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Acknowledgment

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

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  1. Department of Diabetes, Endocrinology and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA

    Samuel Rahbar

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Correspondence to Samuel Rahbar.

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Rahbar, S. Novel inhibitors of glycation and AGE formation. Cell Biochem Biophys 48, 147–157 (2007). https://doi.org/10.1007/s12013-007-0021-x

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