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0026-895X/97/010054-09$3.00/0
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
All rights of reproduction in any form reserved.
MOLECULAR PHARMACOLOGY 52:54-62 (1997).

Recombinant Advanced Glycation End Product Receptor Pharmacokinetics in Normal and Diabetic Rats

C. Renard, O. Chappey, M.-P. Wautier, M. Nagashima, E. Lundh, J. Morser, L. Zhao, A.-M. Schmidt, J.-M. Scherrmann, and J.-L. Wautier

Laboratoire de Recherche en Biologie Vasculaire et Cellulaire, EA 1557, Université Paris 7, Hôpital Lariboisière, Paris, France (C.R., O.C., M.-P.W., J.-L.W.), Institut National de la Santé et de la Recherche Médicale Unité 26, Hôpital Fernand Widal, Paris, France (C.R., J.-M.S.), Berlex Biosciences, Richmond, California 94804 (M.N., E.L., J.M., L.Z.), and Department of Physiology, Medicine, and Surgery, Columbia University, College of Physicians and Surgeons, New York 10032 (A.-M.S.)

Vascular dysfunction in patients with diabetes mellitus is related to advanced glycation end product (AGE) formation. We previously showed that AGEs produce an increase in vascular permeability and generated an oxidant stress after binding to the receptor (RAGE) present on endothelium. RAGE, a 35-kDa protein that belongs to the immunoglobulin superfamily, has been cloned from a rat lung cDNA library, and recombinant rat soluble RAGE (rR-RAGE) has been produced in insect cells. The sequence of RAGE is highly conserved between human and rat. We studied the biological effect of rR-RAGE and pharmacokinetics of 125I-rR-RAGE after intravenous or intraperitoneal administration in normal and streptozotocin-induced diabetic rats. rR-RAGE prevented albumin or inulin transfer through a bovine aortic endothelial cell monolayer, restored the hyperpermeability observed in diabetic rats or induced in normal rats by diabetic rat red blood cells, and corrected the reactive oxygen intermediate production after intravenous or intraperitoneal administration. After intravenous injection of 125I-rR-RAGE, the distribution half-life was longer (p <=  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 <=  0.01). Distribution volume was higher in diabetic than in normal rats (6.94 and 3.24 liter/kg, respectively; p = 0.049). Our study showed that rR-RAGE was biologically active in vivo and slowly cleared, which suggests it could be considered as a potential therapy.


Copyright © by The American Society for Pharmacology and Experimental Therapeutics



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