N ε-(Carboxymethyl)Lysine Adducts of Proteins Are Ligands for Receptor for Advanced Glycation End Products That Activate Cell Signaling Pathways and Modulate Gene Expression

Abstract

Recent studies suggested that interruption of the interaction of advanced glycation end products (AGEs), with the signal-transducing receptor receptor for AGE (RAGE), by administration of the soluble, extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated atherosclerosis in diabetic rodents. Since the precise molecular target of soluble RAGE in those settings was not elucidated, we tested the hypothesis that predominant specific AGEs within the tissues in disorders such as diabetes and renal failure,N ε-(carboxymethyl)lysine (CML) adducts, are ligands of RAGE. We demonstrate here that physiologically relevant CML modifications of proteins engage cellular RAGE, thereby activating key cell signaling pathways such as NF-κB and modulating gene expression. Thus, CML-RAGE interaction triggers processes intimately linked to accelerated vascular and inflammatory complications that typify disorders in which inflammation is an established component. Recent studies suggested that interruption of the interaction of advanced glycation end products (AGEs), with the signal-transducing receptor receptor for AGE (RAGE), by administration of the soluble, extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated atherosclerosis in diabetic rodents. Since the precise molecular target of soluble RAGE in those settings was not elucidated, we tested the hypothesis that predominant specific AGEs within the tissues in disorders such as diabetes and renal failure,N ε-(carboxymethyl)lysine (CML) adducts, are ligands of RAGE. We demonstrate here that physiologically relevant CML modifications of proteins engage cellular RAGE, thereby activating key cell signaling pathways such as NF-κB and modulating gene expression. Thus, CML-RAGE interaction triggers processes intimately linked to accelerated vascular and inflammatory complications that typify disorders in which inflammation is an established component. advanced glycation end products AGE-β2-microglobulin bovine serum albumin N ε- (carboxymethyl)lysine dominant negative dialysis-related amyloidosis ELISA, enzyme-linked immunosorbent assay electrophoretic mobility shift assay glutathione S-transferase human umbilical vein endothelial cells keyhole limpet hemocyanin mononuclear phagocyte ovalbumin phosphate-buffered saline soluble RAGE receptor for AGE Tris-buffered saline vascular smooth muscle cells polyacrylamide gel electrophoresis Receptor for AGE1(RAGE), a member of the immunoglobulin superfamily, was first described as a cell surface interaction site for advanced glycation end products (AGEs), products of glycation and oxidation of proteins and lipids (1Schmidt A.M. Vianna M. Gerlach M. Brett J. Ryan J. Kao J. Esposito C. Hegarty H. Hurley W. Clauss M. Wang F. Pan Y.C. Tsang T.C. Stern D. J. Biol. Chem. 1992; 267: 14987-14997Abstract Full Text PDF PubMed Google Scholar, 2Neeper M. Schmidt A.M. Brett J. Yan S.D. Wang F. Pan Y.C. Elliston K. Stern D. Shaw A. J. Biol. Chem. 1992; 267: 14998-15004Abstract Full Text PDF PubMed Google Scholar). AGEs are a heterogeneous class of compounds, whose accumulation in disorders such as diabetes, renal failure, Alzheimer's disease, and, indeed, natural aging, albeit to a lesser degree, has suggested their potential contribution to the pathogenesis of complications that typify these conditions (3Brownlee M. Annu. Rev. Med. 1995; 46: 223-234Crossref PubMed Scopus (1174) Google Scholar, 4Brownlee M. Cerami A. Vlassara H. N. Engl. J. Med. 1988; 318: 1315-1320Crossref PubMed Scopus (2405) Google Scholar, 5Palinski W. Koschinsky T. Butler S. Miller E. Vlassara H. Cerami A. Witztum J. Atheroscler. Thromb. Vasc. Biol. 1995; 15: 571-582Crossref PubMed Scopus (138) Google Scholar, 6Miyata T. Oda O. Inagi R. Iida Y. Araki N. Yamada N. Horiuchi S. Taniguchi N. Maeda K. Kinoshita T. J. Clin. Invest. 1993; 92: 1243-1252Crossref PubMed Scopus (413) Google Scholar, 7Takedo A. Yasuda T. Miyata T. Mizuno K. Li M. Yoneyama S. Horie K. Maeda K. Sobue G. Neurosci. Lett. 1996; 221: 17-20Crossref PubMed Scopus (63) Google Scholar). Our previous studies demonstrated that both in vitro and in vivo derived heterogeneous AGEs ligate cell surface RAGE on endothelium (ECs), mononuclear phagocytes (MPs), vascular smooth muscle (VSMC), and neurons to activate cell signaling pathways such as ERK1/ERK2 kinases and NF-κB (8Yan S.D. Schmidt A.M. Anderson G. Zhang J. Brett J. Zou Y.S. Pinsky D. Stern D. J. Biol. Chem. 1994; 269: 9889-9897Abstract Full Text PDF PubMed Google Scholar, 9Lander H.L. Tauras J.M. Ogiste J.S. Hori O. Moss R.A. Schmidt A.M. J. Biol. Chem. 1997; 272: 17810-17814Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar), thereby redirecting cellular function in a manner linked to expression of inflammatory and prothrombotic genes important in the pathogenesis of chronic disorders as apparently diverse as diabetic macrovascular disease and amyloidosis (10Schmidt A.M. Yan S.D. Brett J. Mora R. Stern D. J. Clin. Invest. 1993; 91: 2155-2168Crossref PubMed Scopus (271) Google Scholar, 11Schmidt A.-M. Hasu M. Popov D. Zhang J.H. Yan S.-D. Brett J. Cao R. Kuwabara K. Costache G. Simionescu N. Simionescu M. Stern D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8807-8811Crossref PubMed Scopus (292) Google Scholar, 12Wautier J.L. Wautier M.P. Schmidt A.M. Anderson G.M. Zoukourian C. Capron L. Chappey O. Yan S.D. Brett J. Guillausseau P.J. Stern D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar, S.D. Schmidt A.M. Brett J. G. C. T. Stern D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar, A.M. Hori O. J. Li J. Zhang J. Cao R. Yan S.D. Brett J. Stern D. J. Clin. Invest. 1995; PubMed Scopus Google Scholar, A.M. E. E. Yan S.D. Hori O. Cao R. Brett J. J. 1996; PubMed Scopus Google Scholar, T. Hori O. Zhang J.H. Yan S.D. L. Iida Y. Schmidt A.M. J. Clin. Invest. 1996; PubMed Scopus Google Scholar, A. T. M. T. H. R. M. 1997; PubMed Scopus Google Scholar, J. J. G.M. Schmidt A.M. Full Text Full Text PDF PubMed Scopus Google Scholar, Zoukourian C. Chappey O. Wautier M.P. Guillausseau P.J. Cao R. Hori O. Stern D. Schmidt A.M. J. Clin. Invest. 1996; PubMed Scopus Google Scholar, L. Yan L. Stern D. Schmidt A.M. Med. PubMed Scopus Google Scholar). Our studies suggested that interruption of the interaction of AGEs with RAGE in by administration of soluble RAGE the extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated and in diabetic Zoukourian C. Chappey O. Wautier M.P. Guillausseau P.J. Cao R. Hori O. Stern D. Schmidt A.M. J. Clin. Invest. 1996; PubMed Scopus Google Scholar, L. Yan L. Stern D. Schmidt A.M. Med. PubMed Scopus Google Scholar). the of demonstrated of an of diabetic with with both that AGEs and their interaction with and of cell surface RAGE. of of in such as and a for interaction in the of vascular in diabetes L. Yan L. Stern D. Schmidt A.M. Med. PubMed Scopus Google Scholar). not the precise that of RAGE. We to specific AGE for their to RAGE on the surface of cells such as and in to their in cellular and studies suggested that N ε- (carboxymethyl)lysine (CML) modifications of proteins are predominant AGEs that in vivo 1993; Scopus Google Scholar, S. J. 1995; PubMed Scopus Google Scholar, K. T. H. Y. M. Araki T. S. Horiuchi S. 1996; PubMed Scopus Google Scholar, E. J. Clin. Invest. 1997; PubMed Scopus Google Scholar). serum of CML demonstrated in with diabetes E. J. Clin. Invest. 1997; PubMed Scopus Google Scholar, K. PubMed Scopus Google and renal L. S. 1997; Full Text PDF PubMed Scopus Google Scholar). accumulation of CML was in vascular and diabetic and human K. PubMed Scopus Google Scholar, S. M. T. Araki N. H. Horiuchi S. T. T. K. J. 1995; Google Scholar, J. N. S. T. T. R. K. Horiuchi S. T. Taniguchi N. 1997; Full Text Full Text PDF Scopus Google Scholar, T. S. K. Inagi R. D. Horie K. K. K. Lett. PubMed Scopus Google Scholar, K. Miyata T. Maeda K. Miyata S. S. H. C. Witztum J.L. K. J. Clin. Invest. 1997; PubMed Scopus Google Scholar). these CML with oxidation such as and are with the that processes of proteins J. Biol. Chem. Full Text PDF PubMed Google Scholar), oxidation triggers of CML J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar), thereby a glycation in diabetic and of to both and diabetes O. E. K. PubMed Scopus Google Scholar). suggested that CML modifications as a of of the thereby a for of a in the to of CML J. Clin. Invest. PubMed Scopus Google Scholar). for inflammatory processes that complications of diabetes and renal failure, for such as and inflammatory disease, and dialysis-related amyloidosis T. Oda O. Inagi R. Iida Y. Araki N. Yamada N. Horiuchi S. Taniguchi N. Maeda K. Kinoshita T. J. Clin. Invest. 1993; 92: 1243-1252Crossref PubMed Scopus (413) Google N. S. E. H. M. O. J. Google Scholar, H. 1993; PubMed Scopus Google Scholar). with these previous studies RAGE in the vascular and inflammatory of disorders in which such as indeed, expression of RAGE is in these that in tissues J. Schmidt A.M. Zou Y.S. Yan S.D. E. Pinsky M. M. Shaw A. A. Stern J. 1993; Google Scholar, U. H. A. R. Schmidt A.M. R. Stern D. J. 1995; Google Scholar, A.M. Yan S.D. Stern D. Med. 1995; PubMed Scopus Google Scholar, T. S. 1997; PubMed Scopus Google Scholar, S. C. W. A. Y. C. N. O. T. D. J. M. J. Stern D. Schmidt A.M. Full Text Full Text PDF PubMed Scopus Google Scholar). these suggested that of CML of proteins as potential specific AGE ligands for RAGE was a we that proteins engage cellular RAGE in vitro and in vivo to activate key cell signaling pathways such as the with of gene expression. these CML-RAGE interaction to the of accelerated vascular and inflammatory complications that typify disorders in which inflammation is an established component. limpet hemocyanin bovine serum albumin ovalbumin in and in to was in a of was for proteins the that was K. T. H. Y. M. Araki T. S. Horiuchi S. 1996; PubMed Scopus Google Scholar). in to proteins with a of CML modifications as was in as that of as and of as and as described of proteins phosphate-buffered saline and by as both by of to the in of PubMed Scopus Google and by K. D. J. 1993; Scopus Google Scholar). adducts, of of of of with in and proteins of to by of in was RAGE and and as described O. Brett J. T. Cao R. Zhang J. M. S. D. J. Stern D. Schmidt A.M. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google and the and as to E. J. Clin. Invest. 1997; PubMed Scopus Google Scholar). serum was and of the was as which that not to the was and which in Tris-buffered saline and in of was and Tris-buffered immunosorbent to the of was of the proteins in for in and on the in the of and serum for in and and was a of in as for in and of with to the for and in as these CML modifications of proteins was of with of was human with diabetes, renal failure, in with the of the of for in to and in of of was in of as and human serum albumin was by of for was and by by with was the to of of was proteins as a to electrophoretic of the to on the in the of in for was as in for in and with with for in the and of was the of was in was to glycation by in was and for the end of that the was to was to which human soluble RAGE. the was with of Tris-buffered saline and of of was and was as described of as of with the and of to with of was to in the was to of of and as was soluble RAGE was with by with to a specific of to of the in CML modifications of proteins as proteins the of in and for in the was and by with for with assay was in with the of in the of a of human the for the end of that with as of was in a was the and in a to the of and D. J. Biol. Chem. Full Text PDF PubMed Google with with in the of the and of to RAGE was by of of to that of to the to and that in the of with soluble RAGE, the potential was for to the of was tested as in the with of RAGE as RAGE the domain was site of and in on a and with RAGE to and by and (1Schmidt A.M. Vianna M. Gerlach M. Brett J. Ryan J. Kao J. Esposito C. Hegarty H. Hurley W. Clauss M. Wang F. Pan Y.C. Tsang T.C. Stern D. J. Biol. Chem. 1992; 267: 14987-14997Abstract Full Text PDF PubMed Google Scholar, 2Neeper M. Schmidt A.M. Brett J. Yan S.D. Wang F. Pan Y.C. Elliston K. Stern D. Shaw A. J. Biol. Chem. 1992; 267: 14998-15004Abstract Full Text PDF PubMed Google to in the umbilical vein endothelial cells and as described E. R. C. R. J. Clin. Invest. PubMed Scopus Google Scholar). in in endothelial cell was to serum to with the of cells with RAGE for in was with the of for to cell cells in for by in for with and with for with and in and to on the cell surface for in cell surface was for and with for and of with as of was cells as described A.M. Hori O. J. Li J. Zhang J. Cao R. Yan S.D. Brett J. Stern D. J. Clin. Invest. 1995; PubMed Scopus Google Scholar). as described (10Schmidt A.M. Yan S.D. Brett J. Mora R. Stern D. J. Clin. Invest. 1993; 91: 2155-2168Crossref PubMed Scopus (271) Google in a which cell surface RAGE, in in bovine serum and the as was as cells to the for cells on the surface of the and the was in and cells that the with in and cells with the to in proteins with the of human soluble RAGE for to cells with a human RAGE in which the domain was was as cells with the to is as domain is in the S. C. W. A. Y. C. N. O. T. D. J. M. J. Stern D. Schmidt A.M. Full Text Full Text PDF PubMed Scopus Google Scholar). cells S.D. J. M. H. A. T. M. J. A. G. Stern D. Schmidt A.M. 1996; PubMed Scopus Google Scholar), and vascular smooth muscle cells by H.L. Tauras J.M. Ogiste J.S. Hori O. Moss R.A. Schmidt A.M. J. Biol. Chem. 1997; 272: 17810-17814Abstract Full Text Full Text PDF PubMed Scopus (691) Google with the for in the of with the for and was RAGE as that was J. R. R. PubMed Scopus Google and for NF-κB T. J. Med. 1992; PubMed Scopus Google as described (8Yan S.D. Schmidt A.M. Anderson G. Zhang J. Brett J. Zou Y.S. Pinsky D. Stern D. J. Biol. Chem. 1994; 269: 9889-9897Abstract Full Text PDF PubMed Google Scholar, 9Lander H.L. Tauras J.M. Ogiste J.S. Hori O. Moss R.A. Schmidt A.M. J. Biol. Chem. 1997; 272: 17810-17814Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar). by both with for to of of the was by as of the vein with with the to and the of of was with for to was in Tris-buffered saline and to for was for and the in and for was to for and for was electrophoresis of of of and of gel to was for as was and the of by was to electrophoretic on a gel was a and linked by a was in for by with by with the in the for with and with for the was to for was in studies to in the by of was to the a first in CML modifications in proteins such as we human serum albumin with diabetes, renal failure, by of on by and with and CML of diabetic and renal with with CML accumulation in the serum of with diabetes renal and suggested the of albumin for by CML in studies E. J. Clin. Invest. 1997; PubMed Scopus Google Scholar, K. PubMed Scopus Google Scholar, L. S. 1997; Full Text PDF PubMed Scopus Google Scholar). Thus, was and tested for to RAGE. the of in a of for RAGE was to that heterogeneous (1Schmidt A.M. Vianna M. Gerlach M. Brett J. Ryan J. Kao J. Esposito C. Hegarty H. Hurley W. Clauss M. Wang F. Pan Y.C. Tsang T.C. Stern D. J. Biol. Chem. 1992; 267: 14987-14997Abstract Full Text PDF PubMed Google Scholar). the was on RAGE was by interaction with in the of with was for CML was for by RAGE, as CML not for of to for of was by within RAGE that interaction with RAGE proteins with glutathione S-transferase by expression in E. by to RAGE to and and domain (1Schmidt A.M. Vianna M. Gerlach M. Brett J. Ryan J. Kao J. Esposito C. Hegarty H. Hurley W. Clauss M. Wang F. Pan Y.C. Tsang T.C. Stern D. J. Biol. Chem. 1992; 267: 14987-14997Abstract Full Text PDF PubMed Google Scholar, 2Neeper M. Schmidt A.M. Brett J. Yan S.D. Wang F. Pan Y.C. Elliston K. Stern D. Shaw A. J. Biol. Chem. 1992; 267: 14998-15004Abstract Full Text PDF PubMed Google not RAGE studies and of a of domain suppressed and the domain of RAGE in specific to studies that a dominant in the AGEs of with was CML S. J. 1995; PubMed Scopus Google Scholar). We AGE by of human with relevant of in for of and to demonstrated with by not of to which human RAGE, with was in the of of with not suppressed of to in was for the specific interaction of with RAGE. these studies that CML that of with relevant of RAGE in a specific We to these to those in in vitro cell to RAGE and cellular We demonstrated that heterogeneous those in vitro those human diabetic endothelial function of RAGE A.M. Hori O. J. Li J. Zhang J. Cao R. Yan S.D. Brett J. Stern D. J. Clin. Invest. 1995; PubMed Scopus Google Scholar). Since in RAGE, we to these modifications important of heterogeneous AGEs in cellular by which endothelial function is in the of diabetes is by expression of vascular cell a cell that of mononuclear cells to the M. M. Thromb. 1994; PubMed Scopus Google Scholar). of with ovalbumin of of in cell surface expression of with with of RAGE in interaction of CML with endothelium was demonstrated by of expression in the of of expression by endothelium was by of which for of cells to endothelium was on the of and interaction of with the as by of in the of in the of not of endothelium with of is in to the by T. J. Med. 1992; PubMed Scopus Google Scholar). We demonstrated that of RAGE by heterogeneous AGEs of as demonstrated by electrophoretic mobility shift assay (8Yan S.D. Schmidt A.M. Anderson G. Zhang J. Brett J. Zou Y.S. Pinsky D. Stern D. J. Biol. Chem. 1994; 269: 9889-9897Abstract Full Text PDF PubMed Google Scholar, 9Lander H.L. Tauras J.M. Ogiste J.S. Hori O. Moss R.A. Schmidt A.M. J. Biol. Chem. 1997; 272: 17810-17814Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar). with with cells to of of demonstrated a in of NF-κB as by NF-κB and these of by interaction with RAGE was by the of to the endothelium to and in the of not with was on of NF-κB of NF-κB RAGE as by a of the RAGE, which the was with RAGE of NF-κB of with cells with a dominant negative Since previous studies demonstrated that the of CML vivo is Biol. Google Scholar), was important to that a of of by CML was of endothelial We and of of and we tested to activate of with in in of NF-κB by with in the of and was on of RAGE was demonstrated by suppressed of NF-κB by in the of not by with not these suggested that proteins specific AGEs that cellular in in RAGE. We to the hypothesis that proteins with RAGE on vascular smooth muscle cells (VSMC), as such cells in vascular in diabetes and renal of NF-κB is a by which of and is K. M. F. Y. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). We first tested of CML in to their interaction with RAGE in of of with in and of of NF-κB with in the of with of of of NF-κB was on interaction with RAGE, as demonstrated by in the of and was of with of of in in of NF-κB with cells with and these by RAGE was by of of NF-κB in the of in the of not with was that of CML interaction of these with RAGE on in of thereby a by which function in the of CML of studies that are of RAGE by heterogeneous those in vitro those derived in vivo such as AGEs diabetic AGE-β2-microglobulin and the of with T. Hori O. Zhang J.H. Yan S.D. L. Iida Y. Schmidt A.M. J. Clin. Invest. 1996; PubMed Scopus Google Scholar). was important to CML adducts, in these activate RAGE on cellular and in T. Maeda K. 1995; PubMed Scopus Google Scholar). studies that CML modifications not of to of a CML-RAGE interaction in cells and in W. Koschinsky T. Butler S. Miller E. Vlassara H. Cerami A. Witztum J. Atheroscler. Thromb. Vasc. Biol. 1995; 15: 571-582Crossref PubMed Scopus (138) Google Scholar). We tested the of to activate with of of of in of mononuclear cells that cell surface RAGE of by cellular RAGE as of cells with in of in a manner with was of with in of RAGE signaling was for these on as of cells with a RAGE in of in to was was important to of of in to their to studies that of to in of cells with and by of RAGE as demonstrated by of in the of and with was Recent that in and human of by CML is in the of and of of Biol. Google Scholar). of CML is to in and in for to the of in CML with in We tested the of of of to engage RAGE on mononuclear cells and to cellular with of these to a in cell by RAGE, as by of in the of and with these of to in in of NF-κB by with in the of and of NF-κB by CML was to of RAGE as by of NF-κB in the of not in the of of and with and demonstrated that the NF-κB of RAGE by was of both and in the of of not not by of in vitro suggested that CML adducts, physiologically relevant of of cellular in a of cell of hypothesis was the of to cellular in a first of these we of of studies that in to of a in for in and was with of in the was of in a in expression of with of and was on of vascular RAGE in the by was demonstrated by in which with in both of expression of in the was and of on of expression a by which of vascular RAGE by expression of and, of mononuclear cells to the of specific AGEs and the by which in diverse settings such as renal failure, and inflammation has the of by which cellular by previous studies that those derived in vivo signal-transducing ligands of RAGE. interaction of the of with renal and with cellular RAGE in and of such as T. Hori O. Zhang J.H. Yan S.D. L. Iida Y. Schmidt A.M. J. Clin. Invest. 1996; PubMed Scopus Google Scholar). Since studies to in of AGEs such as and T. S. R. Y. Horiuchi S. M. Maeda K. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, T. M. T. T. T. N. Y. T. 1996; Full Text PDF PubMed Scopus Google Scholar, T. T. S. T. T. Miyata T. K. F. N. Y. 1997; Full Text PDF PubMed Scopus Google Scholar), was important to to those specific AGEs that with RAGE. the we that CML adducts, dominant AGEs within the are signal-transducing ligands for RAGE in in endothelial mononuclear and vascular smooth and in we tested of CML to demonstrate that the CML specific and physiologically relevant of CML of ovalbumin of modulating of those in derived human such as and Biol. Google Scholar). We that in a such as and and of CML those tested of are in with diabetes renal Biol. Google Scholar). We that the accumulation of their interaction with RAGE, a in cellular of cellular chronic AGE of RAGE a shift in the cellular with Thus, interaction the first in a of diabetic the the of and the is an in and of these in an cellular processes in diabetic Thus, as to in which by cellular in and of in settings such as diabetes, renal failure, and chronic chronic cellular in important by which AGEs cellular is of by for and of NF-κB (8Yan S.D. Schmidt A.M. Anderson G. Zhang J. Brett J. Zou Y.S. Pinsky D. Stern D. J. Biol. Chem. 1994; 269: 9889-9897Abstract Full Text PDF PubMed Google H.L. Tauras J.M. Ogiste J.S. Hori O. Moss R.A. Schmidt A.M. J. Biol. Chem. 1997; 272: 17810-17814Abstract Full Text Full Text PDF PubMed Scopus (691) Google Scholar), the a cell signaling whose is linked to of a of RAGE J. Schmidt A.M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). We that these suppressed in the of (8Yan S.D. Schmidt A.M. Anderson G. Zhang J. Brett J. Zou Y.S. Pinsky D. Stern D. J. Biol. Chem. 1994; 269: 9889-9897Abstract Full Text PDF PubMed Google Scholar, 9Lander H.L. Tauras J.M. Ogiste J.S. Hori O. Moss R.A. Schmidt A.M. J. Biol. Chem. 1997; 272: 17810-17814Abstract Full Text Full Text PDF PubMed Scopus (691) Google and in RAGE, are and in processes to cellular with these in diabetes, AGEs to within of Zoukourian C. Chappey O. Wautier M.P. Guillausseau P.J. Cao R. Hori O. Stern D. Schmidt A.M. J. Clin. Invest. 1996; PubMed Scopus Google Scholar, L. Yan L. Stern D. Schmidt A.M. Med. PubMed Scopus Google Scholar, and A. A. R. L. PubMed Google Scholar). Thus, not for in diabetes, as by of and in diabetic J. Clin. Invest. 1997; PubMed Scopus Google Scholar), we that in tissues such as the and to by of and CML and chronic RAGE. cellular with of CML in diabetic PubMed Google in relevant accumulation and for the that chronic of relevant in diabetic in to the that the of diabetic such as those in the and with the of CML accumulation J. Clin. Invest. 1993; 91: PubMed Scopus Google Scholar, M. J. E. PubMed Scopus Google Scholar). here not specific AGE products of glycation such as and J. Biol. Chem. Full Text PDF PubMed Google Scholar, PubMed Scopus Google Scholar, P.J. J. Chem. 1995; PubMed Scopus Google as signal-transducing ligands of RAGE. in the tissues is that relevant of these engage cellular RAGE to cellular not the of cellular interaction for CML studies that RAGE is a receptor for is that for AGE H. R. 1996; PubMed Google Scholar, N. T. T. R. Y. T. Y. M. Horiuchi S. J. 1995; PubMed Scopus Google Scholar, J. C. J. S. Cao L. S. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google engage of to the receptor a in of CML adducts, as that pathways to accelerated accumulation of AGEs and is that these products in the of diabetes renal T. C. K. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). cellular for AGEs diverse the receptor has to Y. H. R. H. T. H. M. S. S. J. PubMed Scopus Google Scholar), which not RAGE. in disorders such as renal and diabetes, in the of cellular diabetes, in of the to cellular T. T. R. G. 1994; PubMed Scopus Google Scholar, H. M. D. C. A. T. L. W. L. E. G. 1996; 272: PubMed Scopus Google Scholar). accelerated and accumulation of products of the are in the pathogenesis of diabetic those of the and D. S. A. N. Engl. J. Med. PubMed Scopus Google Scholar). Recent that to of AGEs Y. Araki N. N. J. Horiuchi S. N. 1996; PubMed Scopus Google not diverse pathways and to cellular the diverse by which CML of proteins to oxidation and of and that physiologically relevant of CML in proteins are signal-transducing ligands for RAGE these of and chronic disease to of of cells in inflammatory Our a for the vascular and inflammatory cell that the complications of diverse such as diabetes, renal failure, chronic inflammation and Alzheimer's disease, in which CML and the expression of RAGE is Thus, of specific molecular to interaction of with RAGE a to cellular and, in chronic