Abstract
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 between125I-rH-RAGE and 125I-rR-RAGE pharmacokinetics in rat may be related to differences in potentialO-glycosylation and protease cleavage sites between the two RAGE molecules.
Footnotes
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Send reprint requests to: Prof. Jean-Luc Wautier, INTS, 6 rue Alexandre Cabanel, 757 39 Paris Cedex 15, France. E-mail:wautier{at}ints.fr
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↵1 This work was supported by a North Atlantic Treaty Organization grant (to J.L.W.).
- Abbreviations:
- AGE
- advanced glycation end products
- RAGE
- receptor for AGEs
- rH-RAGE
- recombinant human RAGE
- EC
- endothelial cell
- rR-RAGE
- recombinant rat RAGE
- VCAM-1
- vascular cell adhesion molecule 1
- PAGE
- polyacrylamide gel electrophoresis
- TCA
- trichloroacetic acid
- Fab
- fragment having antigen-binding site
- RBC
- red blood cell
- TBIR
- tissue-blood isotope ratio
- λz
- terminal disposition rate constant
- T1/2λz
- elimination half-life
- AUC
- area under the curve
- CL
- total clearance
- Vz
- volume of distribution of the elimination phase
- Vc
- volume of central compartment
- Ve
- extrapolated volume
- Vss
- distribution volume at steady state
- MRT
- mean residence time
- Cmax
- maximal concentration
- Tmax
- time ofCmax
- Received February 15, 1999.
- Accepted May 24, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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