RECOMBINANT ADVANCED GLYCATION END-PRODUCT RECEPTOR PHARMACOKINETICS IN NORMAL AND DIABETIC RATS

Vascular dysfunction in patients with diabetes mellitus is related to advanced glycation end product (AGE) formation. We previously showed t hat AGEs produce an increase in vascular permeability and generated an oxidant stress after binding to the receptor (RAGE) present on endoth elium. RAGE, a 35-kDa protein that belongs to the immunoglobulin super family, has been cloned from a rat lung cDNA library, and recombinant rat soluble RAGE (rR-RAGE) has been produced in insect cells. The sequ ence of RAGE is highly conserved between human and rat. We studied the biological effect of rR-RAGE and pharmacokinetics of (125)l-rR-RAGE a fter intravenous or intraperitoneal administration in normal and strep tozotocin-induced diabetic rats. rR-RAGE prevented albumin or inulin t ransfer through a bovine aortic endothelial cell monolayer, restored t he hyperpermeability observed in diabetic rats or induced in normal ra ts by diabetic rat red blood cells, and corrected the reactive oxygen intermediate production after intravenous or intraperitoneal administr ation. After intravenous injection of (125)l-rR-RAGE, the distribution half-life was longer (p less than or equal to 0.01) in diabetic (0.15 and 4.01 hr) than in normal (0.02 and 0.21 hr) rats, as was the case for the elimination half-lives (diabetic, 57.17 hr; normal, 26.02 hr; p less than or equal to 0.01). Distribution volume was higher in diabe tic than in normal rats (6.94 and 3.24 liter/kg, respectively; p = 0.0 49). Our study showed that rR-RAGE was biologically active in vivo and slowly cleared, which suggests it could be considered as a potential therapy.