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

  1. C. Renard1,2,
  2. O. Chappey1,
  3. M.-P. Wautier1,
  4. M. Nagashima3,
  5. E. Lundh3,
  6. J. Morser3,
  7. L. Zhao3,
  8. A.-M. Schmidt4,
  9. J.-M. Scherrmann2 and
  10. J.-L. Wautier1
  1. 1Laboratoire 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.), 2Institut National de la Santé et de la Recherche Médicale Unité 26, Hôpital Fernand Widal, Paris, France (C.R., J.-M.S.), 3Berlex Biosciences, Richmond, California 94804 (M.N., E.L., J.M., L.Z.), and4Department of Physiology, Medicine, and Surgery, Columbia University, College of Physicians and Surgeons, New York 10032 (A.-M.S.)

    Abstract

    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 of125I-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.

    Footnotes

    • Send reprint requests to: Dr. Jean-Luc Wautier, I.N.T.S., 6, rue Alexandre Cabanel, 75739 Paris Cedex 15, France.

    • This work was supported by a Research Fellowship (C. R.) provided by Naturalia and Biologia (Paris, France) and a North Atlantic Treaty Organization grant (J.L.W.).

    • Abbreviations:
      AGE
      advanced glycation end product
      EC
      endothelial cell
      RAGE
      receptor for AGE
      sRAGE
      soluble form of RAGE
      RBC
      red blood cell
      rR-RAGE
      recombinant rat RAGE
      TBARS
      thiobarbituric acid-reactive substances
      PBS
      phosphate-buffered saline
      SDS
      sodium dodecyl sulfate
      PAGE
      polyacrylamide gel electrophoresis
      Fab
      fragment antigen binding
      TBIR
      tissue-blood isotope ratio
      TCA
      trichloroacetic acid
      t1/2λ1
      first distribution half-life
      t1/2λ2
      second distribution half-life
      t1/2λz
      elimination half-life
      CL
      total clearance
      Vz
      volume of distribution of the elimination phase
      CLR
      renal clearance
      Sf9
      Spodoptera frugiperda
      • Received December 11, 1996.
      • Accepted March 26, 1997.
    « Previous | Next Article »Table of Contents

    This Article

    1. Molecular Pharmacology July 1, 1997 vol. 52 no. 1 54-62
    1. » Abstract
    2. Full Text
    3. Full Text (PDF)

    Classifications

    Responses

    1. Submit a response
    2. No responses published

    Current Issue

    1. November 2009, 76 (5)
    1. Current Issue
    1. Alert me to new issues of Molecular Pharmacology