Prevention of early renal disease, dyslipidaemia and lipid peroxidation in STZ-diabetic rats by LR-9 and LR-74, novel AGE inhibitors.
BACKGROUND
Increased formation of advanced glycation/lipoxidation endproducts (AGEs/ALEs) has been implicated in the pathogenesis of various diabetic complications. Several compounds have been developed as inhibitors of AGE/ALE formation. We examined the effects of two new AGE/ALE inhibitors, LR-9 and LR-74, on the development of early renal disease and lipid metabolism in streptozotocin (STZ)-induced diabetic rats.


METHODS
Diabetic Sprague-Dawley rats were treated with either of the LR compounds for 32 weeks. Progression of renal disease was evaluated by measurements of urinary albumin and plasma creatinine concentrations. AGE/ALE and nitrotyrosine levels in kidneys were determined by immunohistochemistry. AGE-induced chemical modification of the tail tendon collagen and levels of Nepsilon-(carboxymethyl) and (carboxyethyl)- lysines (CML and CEL) in skin collagen were measured. Plasma lipids and their lipid hydroperoxide concentrations were also determined. In vitro, both compounds were tested for inhibiting lipid peroxidation reactions.


RESULTS
Treatment of either LR compounds significantly inhibited the increase in albuminuria, creatinaemia, hyperlipidaemia and lipid peroxidation in diabetic rats without any effect on hyperglycaemia. Both compounds also reduced CML-AGE and nitrotyrosine accumulation in kidney glomeruli and tubules, AGE-linked fluorescence and cross-linking of tail collagen, and levels of CML and CEL in skin collagen. In vitro, LR compounds inhibited the oxidation of human low-density lipoprotein (LDL).


CONCLUSIONS
Both compounds can inhibit the progression of renal disease and also prevent dyslipidaemia in type-1 diabetic animals. These compounds may have an additional beneficial effect as an antioxidant against lipid peroxidation, and thus may provide alternative therapeutic options for the treatment of various diabetic macrovascular complications.
Figarola
James Lester
JL
Department of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center, Duarte,CA 91010, USA.
Scott
Steven
S
Loera
Sofia
S
Xi
Bixin
B
Synold
Timothy
T
Weiss
Lawrence
L
Rahbar
Samuel
S
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D002087:Butyrates / Q000627:therapeutic use*; D003094:Collagen / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D050171:Dyslipidemias / Q000517:prevention & control*; D017127:Glycation End Products, Advanced / Q000032:analysis / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000737:chemistry; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D011422:Propionates / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D051381:Rats; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
C507130:2-(8-quinolinoxy)propionic acid; C507129:4-(2-naphthylcarboxamido)phenoxyisobutyric acid; D000975:Antioxidants; D002087:Butyrates; D017127:Glycation End Products, Advanced; D009281:Naphthalenes; D011422:Propionates; D011804:Quinolines; C002744:3-nitrotyrosine; D014443:Tyrosine; D003094:Collagen