The human and rat recombinant receptors for advanced glycation end products have a high degree of homology but different pharmacokinetic properties in rats

The accelerated formation of advanced glycation end products (AGEs) is impl icated in diabetic microvascular and macrovascular complications. The bindi ng of AGEs to their cellular surface receptor (RAGE) induces vascular dysfu nction and in particular an increase in vascular permeability. We previousl y demonstrated that rat recombinant RAGE (rR-RAGE)produced in insect cells corrected the hyperpermeability due to RAGE AGE interaction and that pharma cokinetic properties of rR-RAGE after i.v. administration in rats were comp atible with a potential therapeutic use. In the present study, we showed th at recombinant human RAGE (rH-RAGE) had a similar efficacy in inhibiting AG E-induced endothelial, alteration and in reducing the hyperpermeability obs erved in streptozotocin-induced diabetic rats. I-125-rH-RAGE elimination ha lf-life! after i.v. administration was similar in diabetic and normal rats (53.7 +/- 7.6 and 45.3 +/- 4.0 h, respectively). The presence of AGEs is re sponsible for a higher distribution volume in diabetic rats compared with n ormal rats (15.3 +/- 2.7 and 7.7 +/- 0.7 l/kg, respectively). Immunoreactiv e I-125-rH-RAGE decreased move rapidly than did immunoreactive I-125-rR-RAG E. The differences between I-125- rH-RAGE and I-125-rR-RAGE pharmacokinetic s in rat may be related to differences in potential O-glycosylation and pro tease cleavage sites between the two RAGE molecules.