Vascular Biology |
From the College of Physicians and Surgeons, Columbia University, New York, New York, and Institut für Pharmazie und Lebensmittelchemie (M.P.), Abteilung Lebensmittelchemie, Universität Erlangen-Nürnberg, Erlangen, Germany.
Correspondence to Dr Ann Marie Schmidt, College of Physicians and Surgeons, Columbia University, 630 West 168th St, P&S 17-501, New York, NY 10032. E-mail ams11{at}columbia.edu
| Abstract |
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1 (IV) collagen. In mice treated with soluble
RAGE, the numbers of infiltrating inflammatory cells and mRNA levels
for these glomerular cytokines and components of
extracellular matrix were decreased. These data suggest that activation
of RAGE primes cells targeted for perturbation in diabetic tissues by
the induction of proinflammatory mediators.
Key Words: receptor for advanced glycation end products glycation diabetes nephropathy atherosclerosis
| Introduction |
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To examine the effects of RAGE and its ligands on vascular
function, we studied 2 tissues especially susceptible to long-term
complications in diabetes, the aorta and kidney. We have previously
demonstrated that apoE-null mice displayed increased atherosclerotic
lesion area and complexity at the aortic sinus on induction of
diabetes.8 AGE-enriched
diabetic atherosclerotic lesions were characterized by increased
numbers of macrophages and vascular smooth muscle cells
compared with lesions in euglycemic mice, suggesting that
inflammatory responses were accelerated in diabetes. A central role for
RAGE was suggested by the finding that the administration of soluble
RAGE (sRAGE) to diabetic mice caused dose-dependent suppression of the
lesion area and complexity, in parallel with decreased levels of plasma
and tissue AGEs.8
Importantly, multiple reports have suggested that a range of AGEs,
especially
N
-(carboxymethyl)lysine,
accumulate in the glomerulus and interstitium of the diabetic
kidney.9 10
N
-(Carboxymethyl)lysinemodified
adducts of proteins, the most prevalent AGEs found in
vivo,11 12 are
signal-transducing ligands of
RAGE.13 Because accumulation
of AGEs has been linked to sites of enhanced expression of
RAGE,14 it was not
surprising that although RAGE is present at low levels in normal
kidney, its expression is increased in diabetic glomeruli, particularly
within podocytes.15 However,
the recent observation that glomerular macrophage
recruitment occurs in the first days of streptozotocin diabetes in
rats16 has suggested that
inflammatory factors may trigger cellular activation in the
kidney.
These considerations led us to examine the presence of proinflammatory EN-RAGEs and RAGE in macrovascular and kidney tissue in diabetic apoE-null mice and to test the effects of ligand-RAGE blockade. We speculate that accumulating RAGE ligands engaging the receptor trigger inflammatory responses, thereby stimulating cellular activation in organs primed for the development of diabetic complications.
| Methods |
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250 mg/dL), diabetic mice
were treated once daily with murine sRAGE (100 µg/d) that was
prepared, purified, and devoid of endotoxin, as previously
described,7 8 or
equal amounts of vehicle, murine serum albumin (MSA, Sigma).
Treatment was continued until euthanasia, 6 weeks after documentation
of diabetes (
14 weeks of age). Blood was retrieved for preparation
of plasma and red blood cells. Levels of cholesterol
(Boehringer-Mannheim), triglycerides (Sigma), and
glycosylated hemoglobin (EG&G Wallac, Inc) were determined. Diabetic
mice did not demonstrate ketonuria and gained weight during the course
of the study.
Tissue Collection and Preparation
At euthanasia, the kidney and aorta were removed and
stored at -80°C. Aorta was retrieved in its entirety from the
proximal arch to the iliac bifurcation. Tissue was placed in buffered
paraformaldehyde (4%) in preparation for
immunohistochemistry, or lysates were prepared for
immunoblotting by homogenizing tissue
(Brinkmann) in PBS containing complete proteinase inhibitor
(Boehringer-Mannheim). Protein concentrations were measured by
assay (Bio-Rad).
Immunoblotting
Protein extracts were subjected to SDS-PAGE
(Novex/Invitrogen) and transfer of the contents of the gels to
nitrocellulose membranes (Novex/Invitrogen).
Immunoblotting was performed as
described.7 Sites of antibody
binding were identified by using chemiluminescence (ECL,
Amersham-Pharmacia). Molecular weights (approximate) of the bands were
identified by simultaneous electrophoresis of molecular
markers (Amersham). Bands were scanned into a laser densitometer, and
quantification was performed by use of ImageQuant software (Molecular
Dynamics). Antibodies used were as follows: goat anti-human vascular
cell adhesion molecule (VCAM)-1 IgG (0.4 µg/mL, Santa Cruz
Biotechnology), goat anti-rat tissue factor IgG (14 µg/mL, generously
supplied by Drs Walter Kisiel [University of New Mexico,
Albuquerque] and Vijay Rao [University of Texas Health
Sciences at Tyler]), rabbit anti-murine RAGE
IgG8 (4.1 µg/mL), and
rabbit antiEN-RAGE IgG7 (4
µg/mL).
Northern Blotting
Kidney tissue was homogenized in TRIZOL
reagent (Life Technologies), and total RNA was isolated. The
concentration and purity of the RNA were established by measuring
optical absorbance at 260/280 nm (Ultra-spec Plus spectrophotometer;
Amersham-Pharmacia). Total RNA (30 µg) was loaded per well of
denaturing formaldehyde gels by use of reagents provided by Ambion.
Northern blotting was performed as previously
described.13 The cDNAs for
mRNA for
1 (IV) collagen, fibronectin, and
transforming growth factor-ß were provided by Dr F.N. Ziyadeh
(University of Pennsylvania,
Philadelphia).20 To
control for loading and transfer of RNA, membranes were stripped, and a
radiolabeled cDNA probe for mouse ß-actin was
used.
Preparation of Nuclear Extract and EMSA
Nuclear proteins from aortic tissue were extracted by
using an NE-PER extraction kit (Pierce) and subjected to
electrophoretic mobility shift assay
(EMSA).7 13
Samples from binding reactions were loaded onto acrylamide
gels (6%). Gels were dried and exposed to Kodak BioMax MS film at
-80°C for 17 hours.
Immunohistochemistry
Aortas and kidneys were
paraformaldehyde-fixed for 16 hours; paraffin-embedded
sections (5 µm thick) were prepared and subjected to
immunohistochemistry with the following antibodies: goat anti-human
VCAM-1 IgG (2 µg/mL), goat anti-rat tissue factor IgG (14 µg/mL),
and rabbit antiEN-RAGE IgG (40 µg/mL). Respective controls with use
of the indicated species of nonimmune IgG were performed; no specific
immunostaining with control IgGs was observed (data not
shown).
Statistical Analysis
Data are reported as mean±SE. Data were
analyzed by ANOVA and, as indicated, subject to post hoc
comparisons by using 2-tailed t
tests.
| Results |
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14 weeks of age. At euthanasia, aortic tissue in its
entirety, from the proximal arch to the iliac bifurcation, and kidney
tissue were retrieved for analysis of markers of inflammation
and cellular activation.
Consistent with previous observations that
expression of RAGE was increased in diabetic tissue, diabetic mice
displayed an
2.0-fold increase in levels of RAGE antigen
(Mr
55 kDa) in the aorta by immunoblotting after 6 weeks
of diabetes
(Figure 1a
). Immunohistochemistry localized the sites of RAGE
expression to vascular smooth muscle and endothelia, as well as
adherent mononuclear cells (data not shown). The promoter of the gene
encoding RAGE is enriched in functional elements, such as binding sites
for nuclear factor
(NF)-
B.21 Previous
studies in transiently transfected endothelial and
smooth muscle cells bearing luciferase-reporter promoter constructs
have suggested that NF-
B elements within the RAGE promoter are
responsive to a range of inflammatory
stimuli.21 Thus, we tested
whether blockade of RAGE would suppress levels of receptor in diabetic
aorta. Aortic tissue retrieved from mice treated with sRAGE
demonstrated decreased levels of RAGE antigen by
immunoblotting; the expression of RAGE was reduced
nearly to the levels observed in nondiabetic control mice
(Figure 1a
).
|
Because previous studies have demonstrated an increased
accumulation of vascular AGEs in
diabetes,8 we tested the
concept that induction of diabetes was associated with increased
expression of proinflammatory EN-RAGEs in aortic tissue. Levels of
EN-RAGE antigen
(Mr
12 kDa) were enhanced
2.5-fold in diabetic aortas compared with
control aortas
(Figure 1b
). That RAGE was importantly involved in
diabetes-associated increases in aortic EN-RAGEs was supported by the
finding that levels of EN-RAGEs were reduced in sRAGE-treated diabetic
aorta
(Figure 1b
). Immunohistochemistry studies localized sites of
EN-RAGE expression to inflammatory cells, such as mononuclear
phagocytes and polymorphonuclear leukocytes, infiltrating the
vascular aorta. Increased numbers of EN-RAGEexpressing inflammatory
cells were adherent to the aortic endothelium in
diabetic mice compared with control mice (online Figure
I; please see
http://atvb.ahajournals.org). In the presence of sRAGE, numbers of
EN-RAGEexpressing inflammatory cells adherent to aortic
endothelium were significantly decreased (Figure
I).
The attraction of increased numbers of EN-RAGEexpressing
inflammatory cells to the diabetic aorta suggested that levels of
proinflammatory adhesion molecules were enhanced in diabetes. Because
ligation of RAGE by either AGEs or EN-RAGEs was previously linked to
transcriptional/translational regulation of VCAM-1 in
vitro,3 22 we
assessed expression of this adhesion molecule in vivo. An
2.6-fold
increase in VCAM-1 antigen
(Mr
95 kDa) was observed by immunoblotting in diabetic
aortas compared with control aortas
(Figure 2
). Immunohistochemical analysis of aortic
tissue with the use of antiVCAM-1 IgG supported these findings and
localized the VCAM-1 antigen to endothelia and vascular smooth muscle
(online Figures III and II, respectively; please see
http://atvb.ahajournals.org). A central role for RAGE in
diabetes-associated upregulation of proinflammatory adhesion molecules
was supported by suppression of levels of VCAM-1 in diabetic mice
treated with sRAGE
(Figure 2a
and online Figure
IV, which can be accessed at
http://atvb.ahajournals.org).
|
A key feature of diabetic vascular lesions is their enhanced
vulnerability to
rupture,23 24
mediated, at least in part, by the generation of procoagulant
molecules. To begin to address this concept in murine models, we
assessed levels of tissue factor, the key initiator of the procoagulant
pathway in vivo.25 Tissue
factor antigen
(Mr
44 kDa) in the aorta was increased
1.7-fold by
immunoblotting in diabetic versus control tissue
(Figure 3
). That RAGE was an important mediator of increased
levels of tissue factor in the aorta was demonstrated by its
suppression to basal levels in diabetic mice treated with sRAGE
(Figure 3
). Immunohistochemistry localized tissue factor to
vascular cells and monocytes in the aorta (Figures V, VI, and VII;
please see http://atvb.ahajournals.org). Although these findings do not
establish a role for tissue factor in the stability of murine
atherosclerotic lesions, they suggest that enhanced generation of
tissue factor reflects activation of multiple proinflammatory
mechanisms in the vessel wall.
|
We next sought to determine the molecular mechanisms
underlying the enhanced expression of inflammatory mediators in
vascular tissue. Previous studies linked the activation of RAGE, by
either AGEs13 or
EN-RAGES,7 to enhanced
nuclear translocation of
NF-
B.26 Compared with
nuclear extracts prepared from nondiabetic aorta, diabetic nuclear
extracts displayed an
1.5-fold increase in the activation of NF-
B
by EMSA with the use of a radiolabeled consensus probe for NF-
B
(Figure 4
, lanes 1 to 6 and 7 to 12, respectively).
Consistent with an important role for RAGE in mediating
enhanced activation of NF-
B in vascular tissue, nuclear extracts
prepared from aorta retrieved from sRAGE-treated diabetic mice revealed
levels of NF-
B nearly identical to those derived from nondiabetic
mice
(Figure 4
, lanes 13 to 18).
|
These findings suggested that macrovascular tissue in diabetes displays accelerated inflammation that is, at least in part, due to the activation of RAGE. To determine whether RAGE-mediated proinflammatory events occurred in other tissues susceptible to diabetic complications, we tested the premise that engagement of RAGE and its ligands might mediate cellular activation in kidney tissue.
Compared with levels in nondiabetic mice, levels of RAGE and
EN-RAGE antigens were increased
1.4- and 3.6-fold in diabetic kidney
(Figure 5a
and 5b
, respectively). The receptor was
importantly involved in enhancing the expression of these molecules,
inasmuch as levels of RAGE and EN-RAGEs were diminished in diabetic
mice treated with sRAGE
(Figure 5a
and 5b
, respectively). Immunohistochemistry
revealed that EN-RAGEs were expressed largely in inflammatory cells
infiltrating diabetic glomeruli at significantly increased numbers
compared with control cells (online Figure
VIII; please see
http://atvb.ahajournals.org). However, in the presence of sRAGE, levels
of infiltrating inflammatory cells were significantly reduced, nearly
to those levels observed in nondiabetic glomeruli (Figure
VIII).
|
Consistent with the observation that increased
numbers of inflammatory cells were identified infiltrating diabetic
glomeruli, levels of VCAM-1 antigen were increased
5.9-fold in
diabetic kidneys compared with control kidneys
(Figure 6
). RAGE was importantly involved in modulating the
expression of VCAM-1, inasmuch as an
44% decrease in levels of
VCAM-1 in the kidney was observed in diabetic mice treated with sRAGE
(Figure 6
). Similar to observations in the aorta, levels of
tissue factor antigen in diabetic kidney were increased
1.5-fold, in
a manner suppressed by sRAGE
(Figure 7
). Immunohistochemistry revealed that compared with
nondiabetic or sRAGE-treated diabetic conditions, diabetes was
associated with increased expression of tissue factor in the glomerulus
and tubular epithelium (online Figures IX, X, and XI; please see
http://atvb.ahajournals.org).
|
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The observation that increased numbers of
EN-RAGEexpressing inflammatory cells were recruited to the diabetic
kidney, along with increased expression of VCAM-1 and tissue factor,
suggested that inflammatory events might alter central properties in
the glomerulus. To test this, we performed Northern blotting to assess
key cytokines and growth factors implicated in the pathogenesis
of diabetic
nephropathy.27 28
Compared with control kidney tissue, tissue retrieved from diabetic
mice displayed an
1.7-, 2.0-, and 3.8-fold increase in mRNA for
transforming growth factor-ß,
1 (IV)
collagen, and fibronectin (online Figures XII, XIII, and XIV,
respectively; please see http://atvb.ahajournals.org). In the presence
of sRAGE, levels of mRNA for these molecules were suppressed compared
with levels observed in nondiabetic controls (Figures XII, XIII, and
XIV, respectively).
Levels of glycosylated hemoglobin, serum cholesterol, and triglycerides did not differ between diabetic mice treated with sRAGE versus vehicle, MSA (data not shown).
| Discussion |
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Consistent with our findings, studies in
Sprague-Dawley rats have demonstrated glomerular
macrophage recruitment in early streptozotocin-induced
diabetes.16 The numbers of
infiltrating macrophages increased in parallel with enhanced
mRNA levels of
1 (IV) collagen. In irradiated
or insulin-treated animals, however, the numbers of recruited
macrophages were reduced, again, in parallel with mRNA levels
for
1 (IV) collagen. In the present
studies, levels of glucose and glycosylated hemoglobin were unchanged
in the presence of RAGE blockade, despite observed decreases in
inflammatory cell recruitment and mRNA for extracellular matrix
molecules, such as
1 (IV) collagen and
fibronectin. Because this and previous work have indicated that the
blockade of RAGE prevents increased expression of the receptor and its
ligands in diabetic tissues, our findings suggest that glucose/oxidant
stressmediated generation of AGEs, their interaction with cellular
RAGE, and subsequent inflammatory events that, at least in part,
involve EN-RAGEs represent critical steps in the cascade of
events stimulating cellular activation in diabetic blood vessels and
glomeruli. Importantly, examination of human kidney biopsies, compared
with age-matched control kidneys, has revealed increased numbers of
glomerular macrophages in mild and moderate
glomerulosclerosis, thus suggesting roles for
inflammatory events in the pathogenesis of human diabetic
nephropathy.34
Consistent with the concept that RAGE mediates
chronic cellular activation in diabetic tissues, nuclear extracts
prepared from diabetic aorta, compared with nondiabetic control aorta,
displayed enhanced activation of NF-
B by EMSA. In striking contrast
to settings such as acute stimulation by lipopolysaccharide or
cytokines, for example, in which activation of NF-
B rises
rapidly, but
transiently,35 36
diabetic vasculature demonstrates sustained activation of
NF-
B. Although activated NF-
B is evident in
euglycemic atherosclerotic
lesions,37 this process
appears enhanced in diabetic vasculature, mediated, in large part, by
the activation of RAGE.
Taken together, our present data demonstrate that blockade of RAGE in diabetic apoE-null mice suppresses the expression of 2 key mediators of vascular inflammation and activation, VCAM-1 and tissue factor, in parallel with decreased expression of RAGE and EN-RAGEs in aorta and kidney. These findings underscore important roles for ligand-RAGEmediated inflammatory responses in diabetic tissues and point to unifying molecular mechanisms in the pathogenesis of seemingly diverse complications in the activated diabetic macrovasculature and kidney.
| Acknowledgments |
|---|
Received November 29, 2000; accepted March 8, 2001.
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G. Marsche, B. Weigle, W. Sattler, and E. Malle Soluble RAGE blocks scavenger receptor CD36-mediated uptake of hypochlorite-modified low-density lipoprotein FASEB J, October 1, 2007; 21(12): 3075 - 3082. [Abstract] [Full Text] [PDF] |
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P. Lewis, N. Stefanovic, J. Pete, A. C. Calkin, S. Giunti, V. Thallas-Bonke, K. A. Jandeleit-Dahm, T. J. Allen, I. Kola, M. E. Cooper, et al. Lack of the Antioxidant Enzyme Glutathione Peroxidase-1 Accelerates Atherosclerosis in Diabetic Apolipoprotein E-Deficient Mice Circulation, April 24, 2007; 115(16): 2178 - 2187. [Abstract] [Full Text] [PDF] |
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D. Foell, H. Wittkowski, T. Vogl, and J. Roth S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules J. Leukoc. Biol., January 1, 2007; 81(1): 28 - 37. [Abstract] [Full Text] [PDF] |
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C. Cuccurullo, A. Iezzi, M. L. Fazia, D. De Cesare, A. Di Francesco, R. Muraro, R. Bei, S. Ucchino, F. Spigonardo, F. Chiarelli, et al. Suppression of Rage as a Basis of Simvastatin-Dependent Plaque Stabilization in Type 2 Diabetes Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2716 - 2723. [Abstract] [Full Text] [PDF] |
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Y. Zhong, S.-H. Li, S.-M. Liu, P. E. Szmitko, X.-Q. He, P. W.M. Fedak, and S. Verma C-Reactive Protein Upregulates Receptor for Advanced Glycation End Products Expression in Human Endothelial Cells Hypertension, September 1, 2006; 48(3): 504 - 511. [Abstract] [Full Text] [PDF] |
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H. Liu, F. Zheng, Z. Li, J. Uribarri, B. Ren, R. Hutter, J. R. Tunstead, J. Badimon, G. E. Striker, and H. Vlassara Reduced Acute Vascular Injury and Atherosclerosis in Hyperlipidemic Mice Transgenic for Lysozyme Am. J. Pathol., July 1, 2006; 169(1): 303 - 313. [Abstract] [Full Text] [PDF] |
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M. A. Reddy, S.-L. Li, S. Sahar, Y.-S. Kim, Z.-G. Xu, L. Lanting, and R. Natarajan Key Role of Src Kinase in S100B-induced Activation of the Receptor for Advanced Glycation End Products in Vascular Smooth Muscle Cells J. Biol. Chem., May 12, 2006; 281(19): 13685 - 13693. [Abstract] [Full Text] [PDF] |
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A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF] |
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J. Steffel, T. F. Luscher, and F. C. Tanner Tissue Factor in Cardiovascular Diseases: Molecular Mechanisms and Clinical Implications Circulation, February 7, 2006; 113(5): 722 - 731. [Abstract] [Full Text] [PDF] |
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M. M. McCormick, F. Rahimi, Y. V. Bobryshev, K. Gaus, H. Zreiqat, H. Cai, R. S. A. Lord, and C. L. Geczy S100A8 and S100A9 in Human Arterial Wall: IMPLICATIONS FOR ATHEROGENESIS J. Biol. Chem., December 16, 2005; 280(50): 41521 - 41529. [Abstract] [Full Text] [PDF] |
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R. Ramasamy, S. J. Vannucci, S. S. D. Yan, K. Herold, S. F. Yan, and A. M. Schmidt Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation Glycobiology, July 1, 2005; 15(7): 16R - 28R. [Abstract] [Full Text] [PDF] |
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B. I. Hudson, E. Harja, B. Moser, and A. M. Schmidt Soluble Levels of Receptor for Advanced Glycation Endproducts (sRAGE) and Coronary Artery Disease: The Next C-Reactive Protein? Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 879 - 882. [Full Text] [PDF] |
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S. J. Zieman, V. Melenovsky, and D. A. Kass Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 932 - 943. [Abstract] [Full Text] [PDF] |
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C. Falcone, E. Emanuele, A. D'Angelo, M. P. Buzzi, C. Belvito, M. Cuccia, and D. Geroldi Plasma Levels of Soluble Receptor for Advanced Glycation End Products and Coronary Artery Disease in Nondiabetic Men Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 1032 - 1037. [Abstract] [Full Text] [PDF] |
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B. Stratmann and D. Tschoepe Pathobiology and cell interactions of platelets in diabetes Diabetes and Vascular Disease Research, February 1, 2005; 2(1): 16 - 23. [Abstract] [PDF] |
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L. L. RONG, W. TROJABORG, W. QU, K. KOSTOV, S. D. YAN, C. GOOCH, M. SZABOLCS, A. P. HAYS, and A. M. SCHMIDT Antagonism of RAGE suppresses peripheral nerve regeneration FASEB J, December 1, 2004; 18(15): 1812 - 1817. [Abstract] [Full Text] [PDF] |
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N. Lamharzi, C. B. Renard, F. Kramer, S. Pennathur, J. W. Heinecke, A. Chait, and K. E. Bornfeldt Hyperlipidemia in Concert With Hyperglycemia Stimulates the Proliferation of Macrophages in Atherosclerotic Lesions: Potential Role of Glucose-Oxidized LDL Diabetes, December 1, 2004; 53(12): 3217 - 3225. [Abstract] [Full Text] [PDF] |
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A. Kosaki, T. Hasegawa, T. Kimura, K. Iida, J. Hitomi, H. Matsubara, Y. Mori, M. Okigaki, N. Toyoda, H. Masaki, et al. Increased Plasma S100A12 (EN-RAGE) Levels in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5423 - 5428. [Abstract] [Full Text] [PDF] |
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D. W. Sommeijer, A. Beganovic, C. G. Schalkwijk, H. Ploegmakers, C. M. van der Loos, B. E. van Aken, H. ten Cate, and A. C. van der Wal More Fibrosis and Thrombotic Complications but Similar Expression Patterns of Markers for Coagulation and Inflammation in Symptomatic Plaques from DM2 Patients J. Histochem. Cytochem., September 1, 2004; 52(9): 1141 - 1149. [Abstract] [Full Text] [PDF] |
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G. Basta, A. M. Schmidt, and R. De Caterina Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes Cardiovasc Res, September 1, 2004; 63(4): 582 - 592. [Abstract] [Full Text] [PDF] |
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C. Lu, J. C. He, W. Cai, H. Liu, L. Zhu, and H. Vlassara Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells PNAS, August 10, 2004; 101(32): 11767 - 11772. [Abstract] [Full Text] [PDF] |
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M. Lassila, K. K. Seah, T. J. Allen, V. Thallas, M. C. Thomas, R. Candido, W. C. Burns, J. M. Forbes, A. C. Calkin, M. E. Cooper, et al. Accelerated Nephropathy in Diabetic Apolipoprotein E-Knockout Mouse: Role of Advanced Glycation End Products J. Am. Soc. Nephrol., August 1, 2004; 15(8): 2125 - 2138. [Abstract] [Full Text] [PDF] |
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Y. Naka, L. G. Bucciarelli, T. Wendt, L. K. Lee, L. L. Rong, R. Ramasamy, S. F. Yan, and A. M. Schmidt RAGE Axis: Animal Models and Novel Insights Into the Vascular Complications of Diabetes Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1342 - 1349. [Abstract] [Full Text] [PDF] |
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Y. Chen, S. S. Yan, J. Colgan, H.-P. Zhang, J. Luban, A. M. Schmidt, D. Stern, and K. C. Herold Blockade of Late Stages of Autoimmune Diabetes by Inhibition of the Receptor for Advanced Glycation End Products J. Immunol., July 15, 2004; 173(2): 1399 - 1405. [Abstract] [Full Text] [PDF] |
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S.-F. Yan, R. Ramasamy, L. G Bucciarelli, T. Wendt, L. K Lee, B. I Hudson, D. M Stenr, E. Lalla, S. Du Yan, L. L. Rong, et al. RAGE and its ligands: a lasting memory in diabetic complications? Diabetes and Vascular Disease Research, May 1, 2004; 1(1): 10 - 20. [Abstract] [PDF] |
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R. Candido, T. J. Allen, M. Lassila, Z. Cao, V. Thallas, M. E. Cooper, and K. A. Jandeleit-Dahm Irbesartan but Not Amlodipine Suppresses Diabetes-Associated Atherosclerosis Circulation, March 30, 2004; 109(12): 1536 - 1542. [Abstract] [Full Text] [PDF] |
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P. Delafontaine, Y.-H. Song, and Y. Li Expression, Regulation, and Function of IGF-1, IGF-1R, and IGF-1 Binding Proteins in Blood Vessels Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 435 - 444. [Abstract] [Full Text] |
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K. C.B. Tan, W.-S. Chow, S. Tam, R. Bucala, and J. Betteridge Association Between Acute-Phase Reactants and Advanced Glycation End Products in Type 2 Diabetes Diabetes Care, January 1, 2004; 27(1): 223 - 228. [Abstract] [Full Text] [PDF] |
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S. F. Yan, R. Ramasamy, Y. Naka, and A. M. Schmidt Glycation, Inflammation, and RAGE: A Scaffold for the Macrovascular Complications of Diabetes and Beyond Circ. Res., December 12, 2003; 93(12): 1159 - 1169. [Abstract] [Full Text] [PDF] |
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T. Chavakis, A. Bierhaus, N. Al-Fakhri, D. Schneider, S. Witte, T. Linn, M. Nagashima, J. Morser, B. Arnold, K. T. Preissner, et al. The Pattern Recognition Receptor (RAGE) Is a Counterreceptor for Leukocyte Integrins: A Novel Pathway for Inflammatory Cell Recruitment J. Exp. Med., November 17, 2003; 198(10): 1507 - 1515. [Abstract] [Full Text] [PDF] |
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F. Cipollone, A. Iezzi, M. Fazia, M. Zucchelli, B. Pini, C. Cuccurullo, D. De Cesare, G. De Blasis, R. Muraro, R. Bei, et al. The Receptor RAGE as a Progression Factor Amplifying Arachidonate-Dependent Inflammatory and Proteolytic Response in Human Atherosclerotic Plaques: Role of Glycemic Control Circulation, September 2, 2003; 108(9): 1070 - 1077. [Abstract] [Full Text] [PDF] |
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R. B. Santana, L. Xu, H. B. Chase, S. Amar, D. T. Graves, and P. C. Trackman A Role for Advanced Glycation End Products in Diminished Bone Healing in Type 1 Diabetes Diabetes, June 1, 2003; 52(6): 1502 - 1510. [Abstract] [Full Text] [PDF] |
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T. Wendt, N. Tanji, J. Guo, B. I. Hudson, A. Bierhaus, R. Ramasamy, B. Arnold, P. P. Nawroth, S. F. Yan, V. D'Agati, et al. Glucose, Glycation, and RAGE: Implications for Amplification of Cellular Dysfunction in Diabetic Nephropathy J. Am. Soc. Nephrol., May 1, 2003; 14(5): 1383 - 1395. [Abstract] [Full Text] [PDF] |
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D. A. Kass Getting Better Without AGE: New Insights Into the Diabetic Heart Circ. Res., April 18, 2003; 92(7): 704 - 706. [Full Text] [PDF] |
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R. Candido, J. M. Forbes, M. C. Thomas, V. Thallas, R. G. Dean, W. C. Burns, C. Tikellis, R. H. Ritchie, S. M. Twigg, M. E. Cooper, et al. A Breaker of Advanced Glycation End Products Attenuates Diabetes-Induced Myocardial Structural Changes Circ. Res., April 18, 2003; 92(7): 785 - 792. [Abstract] [Full Text] [PDF] |
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M. Morcos, A. A.R. Sayed, A. Bierhaus, B. Yard, R. Waldherr, W. Merz, I. Kloeting, E. Schleicher, S. Mentz, R. F. Abd el Baki, et al. Activation of Tubular Epithelial Cells in Diabetic Nephropathy Diabetes, December 1, 2002; 51(12): 3532 - 3544. [Abstract] [Full Text] [PDF] |
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L. G. Bucciarelli, T. Wendt, W. Qu, Y. Lu, E. Lalla, L. L. Rong, M. T. Goova, B. Moser, T. Kislinger, D. C. Lee, et al. RAGE Blockade Stabilizes Established Atherosclerosis in Diabetic Apolipoprotein E-Null Mice Circulation, November 26, 2002; 106(22): 2827 - 2835. [Abstract] [Full Text] [PDF] |
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R. Candido, K. A. Jandeleit-Dahm, Z. Cao, S. P. Nesteroff;, W. C. Burns, S. M. Twigg, R. J. Dilley, M. E. Cooper, and T. J. Allen Prevention of Accelerated Atherosclerosis by Angiotensin-Converting Enzyme Inhibition in Diabetic Apolipoprotein E-Deficient Mice Circulation, July 9, 2002; 106(2): 246 - 253. [Abstract] [Full Text] [PDF] |
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L. R. James, D. Tang, A. Ingram, H. Ly, K. Thai, L. Cai, and J. W. Scholey Flux Through the Hexosamine Pathway Is a Determinant of Nuclear Factor {kappa}B- Dependent Promoter Activation Diabetes, April 1, 2002; 51(4): 1146 - 1156. [Abstract] [Full Text] [PDF] |
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