Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice

Vascular complications arising from multiple environmental and genetic fact ors are responsible for many of the disabilities and short life expectancy associated with diabetes mellitus, Here we provide the first direct in vivo evidence that interactions between advanced glycation end products (AGEs; nonenzymatically glycosylated protein derivatives formed during prolonged h yperglycemic exposure) and their receptor, RAGE, lead to diabetic vascular derangement. Wie created transgenic mice that overexpress human RAGE in vas cular cells and crossbred them with another transgenic line that develops i nsulin-dependent diabetes shortly after birth. The resultant double transge nic mice exhibited increased hemoglobin A(1c) and serum AGE levels, as did the diabetic controls. The double transgenic mice demonstrated enlargement of the kidney, glomerular hypertrophy, increased albuminuria, mesangial exp ansion, advanced glomerulosclerosis, and increased serum creatinine compare d with diabetic littermates lacking the RAGE transgene. To our knowledge, t he development of this double transgenic mouse provides the first animal mo del that exhibits the renal changes seen in humans. Furthermore, the phenot ypes of advanced diabetic nephropathy were prevented by administering an AG E inhibitor, (+/-)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanil ide(OPB-9195), thus establishing the AGE-RAGE system as a promising target for overcoming this aspect of diabetic pathogenesis.