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 implicated in diabetic microvascular and macrovascular complications. The binding of AGEs to their cellular surface receptor (RAGE) induces vascular dysfunction and in particular an increase in vascular permeability. We previously demonstrated that rat recombinant RAGE (rR-RAGE) produced in insect cells corrected the hyperpermeability due to RAGE-AGE interaction and that pharmacokinetic properties of rR-RAGE after i.v. administration in rats were compatible with a potential therapeutic use. In the present study, we showed that recombinant human RAGE (rH-RAGE) had a similar efficacy in inhibiting AGE-induced endothelial alteration and in reducing the hyperpermeability observed in streptozotocin-induced diabetic rats. (125)I-rH-RAGE elimination half-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 responsible for a higher distribution volume in diabetic rats compared with normal rats (15.3 +/- 2.7 and 7.7 +/- 0. 7 l/kg, respectively). Immunoreactive (125)I-rH-RAGE decreased more rapidly than did immunoreactive (125)I-rR-RAGE. The differences between (125)I-rH-RAGE and (125)I-rR-RAGE pharmacokinetics in rat may be related to differences in potential O-glycosylation and protease cleavage sites between the two RAGE molecules.
Renard
C
C
Laboratoire de Recherche en Biologie Vasculaire et Cellulaire, EA 1557, Hôpital Lariboisière, Paris Cedex, France.
Chappey
O
O
Wautier
M P
MP
Nagashima
M
M
Morser
J
J
Scherrmann
J M
JM
Wautier
J L
JL
D000418:Albumins / Q000493:pharmacokinetics; D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000378:metabolism; D002199:Capillary Permeability / Q000502:physiology; D002417:Cattle; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D014238:Trichloroacetic Acid / Q000494:pharmacology
D000418:Albumins; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014238:Trichloroacetic Acid