lr-90 and Dyslipidemias

Previous studies have shown that LR-90, a new inhibitor of AGE formation, prevented the development of experimental type 1 diabetic nephropathy. In this study, we examined the effects of LR-90 in the Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes and metabolic syndrome, and investigated the mechanisms by which it may protect against renal injury.. Male ZDF rats were treated without or with LR-90 from age 13 to 40 weeks. Metabolic and kidney functions and renal histology were evaluated. AGE accumulation and the production of the receptor for AGE (AGER) were measured. Profibrotic growth factors, extracellular matrix proteins and intracellular signalling pathways associated with glomerular and tubular damage were also analysed.. LR-90 dramatically reduced plasma lipids in ZDF rats, with only modest effects on hyperglycaemia. Renal AGE, AGER and lipid peroxidation were all attenuated by LR-90. LR-90 significantly retarded the increase in albuminuria and proteinuria. This was associated with reduction in glomerulosclerosis and tubulointerstitial fibrosis, concomitant with marked inhibition of renal overproduction of TGF-beta1, connective tissue growth factor, fibronectin and collagen IV. Additionally, LR-90 downregulated the activation of key mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-kappaB) in the renal cortex.. These results support our earlier studies on the renoprotective effects of LR-90 on type 1 diabetic nephropathy and provide further evidence that LR-90, an AGE inhibitor with pleiotrophic effects, may also be beneficial for the prevention of type 2 diabetic nephropathy, where multiple risk factors, such as hyperglycaemia, dyslipidaemia, obesity, insulin resistance and hypertension, contribute to renal injury.

Topics: Animals; Blood Glucose; Blood Pressure; Butyrates; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dyslipidemias; Heart Rate; Kidney; Kidney Function Tests; Rats; Rats, Zucker; Triglycerides

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.

Topics: Animals; Ascorbic Acid; Body Weight; Butyrates; Cholesterol; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dyslipidemias; Glycation End Products, Advanced; Glycosylation; Hydroxyl Radical; Hypoglycemic Agents; Kidney; Lipid Metabolism; Lipoproteins, LDL; Male; Molecular Structure; Oxidation-Reduction; Pyridoxal Phosphate; Rats; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Triglycerides; Tyrosine