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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.
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