Novel inhibitors of glycation and AGE formation.
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.
Rahbar
Samuel
S
Department of Diabetes, Endocrinology and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA. srahbar@coh.org
D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry; D001835:Body Weight / Q000187:drug effects; D002087:Butyrates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D050171:Dyslipidemias / Q000097:blood; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D017665:Hydroxyl Radical / Q000737:chemistry; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000737:chemistry; D008297:Male; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D011732:Pyridoxal Phosphate / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D002087:Butyrates; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; C485003:LR-90; D008077:Lipoproteins, LDL; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014280:Triglycerides; D017665:Hydroxyl Radical; C002744:3-nitrotyrosine; D014443:Tyrosine; D011732:Pyridoxal Phosphate; D002784:Cholesterol; D003404:Creatinine; D001205:Ascorbic Acid