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Vol. 290, Issue 3, 1458-1466, September 1999

The Human and Rat Recombinant Receptors for Advanced Glycation End Products Have a High Degree of Homology but Different Pharmacokinetic Properties in Rats1

C. Renard , O. Chappey, M. P. Wautier, M. Nagashima, J. Morser, J. M. Scherrmann and J. L. Wautier

Laboratoire de Recherche en Biologie Vasculaire et Cellulaire, EA 1557, Hôpital Lariboisière, Paris Cedex, France (C.R., O.C., M.P.W., J.L.W.); Institut National de Transfusion Sanguine, Paris Cedex, France (J.L.W.); Institut National de la Santé et de la Recherche Médicale Unité 26, Hôpital Fernand Widal, Paris Cedex, France (C.R., J.M.S.); and Berlex Biosciences, Richmond, California (M.N., J.M.)

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. 125I-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 125I-rH-RAGE decreased more rapidly than did immunoreactive 125I-rR-RAGE. The differences between 125I-rH-RAGE and 125I-rR-RAGE pharmacokinetics in rat may be related to differences in potential O-glycosylation and protease cleavage sites between the two RAGE molecules.

0022-3565/99/2903-1458$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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