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,
,§
*
Department of Pathology, Columbia University College of Physicians and
Surgeons, New York, New York
Department of Physiology, Columbia University College of Physicians and
Surgeons, New York, New York
Department of Surgery, Columbia University College of Physicians and
Surgeons, New York, New York
§
Department of Medicine, Columbia University College of Physicians and
Surgeons, New York, New York
||
Institut fur Pharmazie und Lebensmittelchemie, Universitat
Erlangen-Nurnberg, Erlangen, Germany
Correspondence to Dr. Vivette D. D'Agati, Department of Pathology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. Phone: 212-305-7460; Fax: 212-342-5380; E-mail: vdd1{at}columbia.edu
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-(carboxymethyl)-lysine (CML) and pentosidine (PENT).
AGE were detected equally in diffuse and nodular diabetic nephropathy. CML was
the major AGE detected in diabetic mesangium (96%), glomerular basement
membranes (GBM) (42%), tubular basement membranes (85%), and vessel walls
(96%). In diabetic nephropathy, PENT was preferentially located in
interstitial collagen (90%) and was less consistently observed in vessel walls
(54%), mesangium (77%), GBM (4%), and tubular basement membranes (31%). RAGE
was expressed on normal podocytes and was upregulated in diabetic nephropathy.
The restriction of RAGE mRNA expression to glomeruli was confirmed by reverse
transcription-PCR analysis of microdissected renal tissue compartments. The
extent of mesangial and GBM immunoreactivity for CML, but not PENT, was
correlated with the severity of diabetic glomerulosclerosis, as assessed
pathologically. CML and PENT were also identified in areas of
glomerulosclerosis and arteriosclerosis in idiopathic and secondary focal
segmental glomerulosclerosis, hypertensive nephrosclerosis, and lupus
nephritis. In active lupus nephritis, CML and PENT were detected in the
proliferative glomerular tufts and crescents. In conclusion, CML is a major
AGE in renal basement membranes in diabetic nephropathy, and its accumulation
involves upregulation of RAGE on podocytes. AGE are also accumulated in acute
inflammatory glomerulonephritis secondary to systemic lupus erythematosus,
possibly via enzymatic oxidation of glomerular matrix proteins. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-(carboxymethyl)lysine (CML) and pentosidine
(PENT). CML can be formed either by oxidative cleavage of fructoselysine or by
reaction of protein with glyoxal, an auto-oxidation product of glucose or a
Schiff base adduct (2). PENT
can be formed from glycoxidation of Amadori products or oxidation of arabinose
(3). The accumulation of these
protein adducts in tissues alters the structure and function of matrix
proteins (4). The accumulation of AGE in kidneys and other tissues of patients with diabetes mellitus has been implicated in the development of diabetic nephropathy and vasculopathy (5,6). AGE may contribute to diabetic tissue injury by at least two major mechanisms. The first is receptor-independent alteration of the extracellular matrix architecture by nonenzymatic glycation and the formation of protein crosslinks. The second mechanism is receptor-dependent and consists of modulation of cellular functions through ligation of specific cell surface receptors, the best characterized of which is the receptor for AGE (RAGE), a member of the Ig superfamily (7,8).
AGE-modified proteins have been demonstrated to stimulate a number of
cellular responses, such as synthesis of fibronectin and type IV collagen by
glomerular mesangial cells
(9,10).
The interaction of AGE with RAGE mediates monocyte migration and activation in
response to AGE
(11,12).
The interaction of AGE with endothelial cell RAGE induces cellular oxidative
stress, hyper-responsiveness to inflammatory cytokines, increased vascular
permeability, and upregulation of cell adhesion molecules
(13,14).
Recent evidence suggests that enhanced interaction of AGE with RAGE may also
be promoted by inflammatory processes and pro-oxidant states. In this context,
AGE-RAGE interaction activates certain signaling pathways that are linked to
altered gene expression, including those involving p21ras, erk1/2
kinases, and NF-
B
(13,15).
Although engagement of AGE with specific receptors on vascular endothelial
cells and macrophages has been demonstrated to play a role in the pathogenesis
of diabetic macrovascular disease
(16), it is not known how
AGE-RAGE interactions might contribute to the development of diabetic
nephropathy.
Little is known regarding the distribution of AGE and RAGE in the kidneys of patients with diffuse or nodular diabetic glomerulosclerosis. To address this issue, we performed an immunohistochemical analysis of AGE and RAGE expression at various stages in the progression of diabetic nephropathy and correlated these findings with clinical and morphologic markers of disease severity. To determine the specificity of these findings for diabetic nephropathy, the results for diabetic nephropathy were compared with those for a variety of nondiabetic renal diseases of sclerosing or inflammatory nature.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The group with diabetic nephropathy consisted of 26 patients with adult-onset diabetes mellitus (18 male and 8 female patients, of whom 11 were Caucasian, 11 were African American, 2 were Hispanic, and 2 were Asian American), with a mean age of 59.7 ± 2.2 yr. Cases were chosen retrospectively from the files of the Nephropathology Laboratory of Columbia University to represent a range of severity of diabetic nephropathy, from mild to advanced. This spectrum is reflected in the wide range of serum creatinine levels, from 0.8 to 11.4 mg/dl (mean, 2.9 ± 0.4 mg/dl), and in the broad range of urinary protein excretion values, from 0.3 to 19.5 g/d (mean, 6.7 ± 0.2 g/d). All renal biopsies were performed between August 1997 and March 1998, and specimens were studied with light microscopy, immunofluorescence microscopy, and electron microscopy, using standard techniques. Diagnoses of diabetic nephropathy were based on the characteristic findings of glomerular basement membrane (GBM) thickening and mesangial sclerosis, as detected using light and electron microscopy (17). Cases included 10 examples of nodular diabetic glomerulosclerosis, 15 cases of diffuse diabetic glomerulosclerosis, and 1 example of the hypertrophic phase of diabetic nephropathy with no recognizable mesangial sclerosis at the light microscopic level. All cases exhibited linear staining of GBM and tubular basement membranes (TBM) with antisera to IgG and albumin. The light and electron microscopic features are listed in Table 1.
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Generation of Specific Antibodies to RAGE, CML, and PENT
Monospecific polyclonal antibodies were raised against human soluble RAGE.
Human soluble RAGE was prepared in a baculovirus expression system, purified
to homogeneity, subjected to aminoterminal sequence analysis, and used to
immunize New Zealand White rabbits. IgG from immunized rabbits was purified
and tested for recognition of RAGE in both enzyme-linked immunosorbent assay
(ELISA) and immunoblotting studies, as described previously
(7,8).
Antibody specificity was confirmed by Western blotting performed with
homogenates of normal human kidney (data not shown).
Affinity-purified antibodies recognizing CML adducts of proteins or PENT-modified adducts were prepared and characterized according to previously published procedures (18,19). CML- or PENT- modified keyhole limpet hemocyanin (KLH) (Sigma Chemical Co., St. Louis, MO) was used to immunize rabbits. Antibodies specific for the KLH backbone were removed by passage of the immune IgG through KLH-preadsorbed Affi-gel resin (Bio-Rad, Hercules, CA). The material not adhering to this column was then chromatographed on Affi-gel resin bearing CML- or PENT-modified bovine serum albumin (BSA) and was eluted with 1 M NaCl. Specificity was tested using ELISA and immunoblotting assays, according to previously published procedures (18,19).
Immunohistochemical Analysis of Renal Biopsy Specimens
Formalin-fixed, paraffin-embedded tissues were cut at 3 µm on
3-aminopropyltriethoxysilane (Sigma)-coated slides, deparaffinized, and
rehydrated in graded alcohols. Sections to be stained with the antibody to
RAGE were heated in a microwave for 25 min before immunostaining. Sections to
be stained with the antibodies to CML or PENT were pretreated with trypsin for
90 min. After blocking with 10% normal goat serum (Vector Laboratories,
Burlingame, CA), serial sections were stained with the antibodies to CML (0.7
µg/ml), PENT (10 µg/ml), or RAGE (4 µg/ml) and were incubated
overnight at 4°C in a humidified chamber. After washing with
phosphate-buffered saline (PBS), sections were stained with biotinylated
secondary goat anti-rabbit antibody (1:100; Vector Laboratories). Sections
were washed with PBS and incubated with avidin-biotin complex (Vector
Laboratories) for 30 min, followed by 3,3'-diaminobenzidine solution
containing 0.003% H2O2. Sections were counterstained
with hematoxylin and mounted. Negative controls consisted of serial sections
stained with equivalent concentrations of preimmune IgG in place of the
primary antibody. To prove the podocytic distribution of RAGE immunostaining,
serial sections were stained with a monoclonal antibody to synaptopodin (Maine
Biotechnology, Portland, ME), a podocyte-specific, actin-associated protein.
After microwave heating, sections were overlaid sequentially with 10% normal
horse serum (Vector Laboratories), synaptopodin-specific antibody (1:1), and
biotinylated horse anti-mouse antibody (1:100; Vector Laboratories). The
combined intensity and distribution of immunostaining were determined on a
scale of 0 to 3+ (0, absent; 1+, low intensity and <25% of structures
stained; 2+, moderate intensity and <50% of structures stained; 3+, high
intensity and >50% of structures stained) for the GBM, mesangium, TBM,
interstitium, and vessels.
Correlations between the prevalence of CML and PENT immunostaining and severity of proteinuria and serum creatinine levels were performed using t tests. Correlations between the grade of immunostaining (0 to 3+) for CML and PENT and the severity of diabetic glomerulosclerosis (assessed histologically) were performed using a doubly ordered contingency table (Jonckheere-Terpstra test) and the linear-by-linear association test.
Laser Capture Microdissection
For the studies of RAGE mRNA expression, snap-frozen, archival, renal
biopsy tissue (which had been stored at -80°C) from patients with diabetic
nephropathy and from normal control subjects was used. The frozen tissue was
cut at 8 µm onto noncoated slides and was rehydrated briefly in graded
alcohols diluted with diethyl pyrocarbonate (DEPC)-treated water. The sections
were stained with Weigert's hematoxylin for 20 s. rinsed briefly in
DEPC-treated water for 5 s, dehydrated in graded alcohols diluted with
DEPC-treated water, immersed in xylene, and air-dried for 20 min. The PixCell
I LCM system (Arcturus Engineering, Mountain View, CA) was used for laser
microdissection. The laser spot size and beam intensity were adjusted to
microdissect pure populations of glomeruli, proximal tubules, and vessels
under direct microscopic observation. For each specimen, 60 individual
glomeruli, 60 individual tubules, and 10 individual vessels were captured
sequentially on separate polymer films. For negative controls, caps were
placed on the tissue sections in the same way but without activation of the
laser pulse.
RNA Extraction and Reverse Transcription (RT)-PCR
Total RNA was extracted using TRI Reagent (Sigma), according to the
single-step method reported by Chomczynski and Sacchi
(20). The RNA was redissolved
in 4 µl of DEPC-treated water, and RT was performed at 60°C for 30 min,
using a GeneAmp EZ rTth RNA PCR kit (Perkin Elmer, Foster City, CA), in a
final volume of 50 µl, with 2 µl of total RNA solution, 0.3 mM levels of
each dNTP, 2.5 mM manganese diacetate, 0.45 µM levels of each primer, and 5
U of rTth DNA polymerase. The sense primer for RAGE corresponded to bp 1801 to
1820 (5'-GCCCTCCAGTACTACTCTCG-3'), and the antisense primer
corresponded to bp 2043 to 2062 (5'-TGTGTGGCCACCCATTCCAG-3'). The
sense and antisense primers for glyceraldehyde-3-phosphate dehydrogenase
corresponded to bp 204 to 226 (5'-CAATGGAAATCCCATCACCATCT-3') and
bp 908 to 930 (5'-AATGAGCTTGACAAAGTGGTCGT-3'), respectively. The
entire RT reaction product was used for PCR amplification. Forty cycles of
amplification were performed with a thermal programmer (Perkin Elmer), as
follows: denaturation at 94°C for 15 s and annealing and extension at
60°C for 30 s. The PCR products were then electrophoresed on a 1.5%
agarose gel stained with ethidium bromide.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunohistochemical Detection of AGE and RAGE in Normal Control
Samples
With the exception of small amounts of CML and PENT in the intima of
medium-sized and large arteries, normal control samples exhibited negative
immunostaining for CML and PENT in the glomerular, tubular, and interstitial
compartments (Figure 1, A and
B). Diffuse low-level expression of RAGE was restricted to the
podocytes of normal control subjects
(Figure 1C).
|
Immunohistochemical Detection of AGE and RAGE in Diabetic
Nephropathy
The immunohistochemical staining results for diabetic nephropathy are
itemized in Table 1 and
summarized in Table 2. CML was
the major AGE identified in the GBM (42% of cases), mesangium (96%), TBM (85%)
of both atrophic and nonatrophic tubules, and vessels (96%)
(Table 2;
Figure 2). Although PENT was
identified in the mesangium in 77% of cases, it was rarely identified in the
GBM (4%) (Figure 3A). Both CML
and PENT were readily identified in mesangial nodules and in areas of
glomerular hyalinosis ("fibrin cap lesions"). In contrast, PENT
was the major AGE identified in areas of subcapsular fibrosis (65%) and
interstitial fibrosis (92%) (Figure 3, B
and C). PENT was less frequently identified in TBM (31%) and
vessel walls (54%), compared with CML. Thus, in diabetic nephropathy, there
was differential localization of PENT to interstitial collagen as well as
mesangium and vascular basement membranes, whereas CML was more restricted to
renal basement membranes known to contain collagen IV. Weak focal tubular
epithelial staining for CML and PENT was identified in patients with moderate
or severe diabetic nephropathy. There was marked uniform upregulation of RAGE
expression in the podocytes of diabetic nephropathy
(Figure 4A). The distribution
of RAGE at the base of the podocytes
(Figure 4B) was confirmed in
serial sections stained for the podocyte-specific marker synaptopodin
(Figure 4C). No RAGE expression
was identified in other renal cell types.
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Correlations between the severity of diabetic nephropathy and the semiquantitative assessments of CML immunostaining in mesangium (P = 0.004), GBM (P < 0.05), and TBM (P = 0.003) were observed. There was no correlation between the severity of diabetic nephropathy and CML immunostaining in globally sclerotic glomeruli, interstitium, or vessel walls (P = NS). In contrast, there were significant correlations between the severity of diabetic nephropathy and the semiquantitative assessments of PENT staining in TBM (P = 0.035) and interstitium (P = 0.037) but not globally sclerotic glomeruli, GBM, mesangium, or vessel walls (P = NS). Among the patients with diabetic nephropathy, no correlation was found between the immunohistochemical quantification of AGE deposition and the severity of proteinuria or renal insufficiency.
RAGE mRNA Expression
The results of RT-PCR for RAGE are shown in
Figure 5. RAGE mRNA expression
was seen in glomeruli, but not tubules or vessels, in renal biopsy tissue from
patients with diabetic nephropathy. No band was identified in glomeruli,
tubules, or vessels from normal control kidney samples (data not shown). No
expression was observed in the negative control samples.
|
Immunohistochemical Detection of AGE and RAGE in Nondiabetic Renal
Diseases
In primary and secondary forms of FSGS and in hypertensive nephrosclerosis,
CML and PENT were commonly detected in the distribution of partially or
globally sclerotic glomeruli (Figure 6, A
and B). However, in contrast to their distribution in diabetic
nephropathy, these AGE were infrequently identified in the mesangium or GBM of
nonsclerotic glomeruli (Table
2). CML and PENT were also present in the TBM of atrophic tubules
but were rarely identified in nonatrophic tubules. In all of these conditions,
CML and PENT staining was common in the vessel walls, particularly the intima
(Figure 6C). CML was
universally identified (100%) in the arteries of hypertensive nephrosclerosis
samples, compared with the 86% prevalence of PENT in vessel walls. PENT, but
not CML, was typically identified in the fibrotic interstitium. In all three
of these sclerosing conditions, the levels of podocyte RAGE were
indistinguishable from those of normal control samples
(Figure 6D).
|
The differences between diabetic nephropathy and primary and secondary forms of FSGS and hypertensive nephrosclerosis were best observed when these categories were dichotomized into subgroups of 2+ or greater immunostaining versus 1+ or no immunostaining. As shown in Table 2, no patient with primary or secondary FSGS or hypertensive nephrosclerosis exhibited 2+ or greater immunostaining for either CML or PENT in the mesangium or GBM of nonsclerotic glomeruli. In contrast, 18 and 31% of diabetic nephropathy biopsies exhibited this level of CML or PENT immunostaining in the GBM and mesangium, respectively, of nonsclerotic glomeruli.
In lupus nephritis, PENT and, to a lesser extent, CML were found in active glomerular necrotizing and inflammatory lesions, including cellular crescents (Figure 7, A to C). However, the uniform distribution of mesangial and GBM staining characteristic of diabetic nephropathy was not observed. The intensity of staining in these active lesions was particularly high, often exceeding that observed for scarred sclerotic glomeruli. Podocyte RAGE expression was focally upregulated in the glomeruli of patients with active lupus nephritis (World Health Organization class IV) (Figure 7D). As shown in Table 2, lupus nephritis was the only category of nondiabetic renal disease studied in which CML or PENT staining of 2+ or more was identified in the mesangium or GBM of nonsclerotic glomeruli. This pattern of staining was most frequently observed in the distribution of active glomerular lesions with endocapillary hypercellularity, infiltrating neutrophils, and necrotizing features.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An unexpected and intriguing finding was the normal distribution of RAGE at the base of the podocytes and its upregulation in diabetic nephropathy but not other sclerosing renal conditions. This podocytic distribution was confirmed by labeling of serial sections with an antibody to the podocytespecific marker synaptopodin. The exclusively glomerular distribution of RAGE immunostaining and its upregulation in diabetic glomeruli was corroborated by the RT-PCR results in microdissected diabetic glomeruli. The failure to detect RAGE mRNA in normal control specimens may be explained by the long-lived nature of the protein in terminally differentiated, quiescent podocytes. Glomerular localization of RAGE was also described by Soulis et al. (23), although the precise cellular localization within glomeruli was not characterized. Although RAGE expression has been reported in vascular endothelial cells of large arteries (6,16), in mononuclear phagocytes (24), and in vascular smooth muscle cells (25), we did not identify RAGE expression, by immunohistochemical analysis, in the renal endothelium, mesangium, or vascular smooth muscle of normal control subjects or patients with diabetic nephropathy. The reason for these discrepancies may be related to the different antibodies and methods used, such as the use of anti-bovine versus anti-human RAGE, the use of frozen versus fixed tissues, and our introduction of microwave treatment for antigen retrieval.
The presence of RAGE on developing neurons of the central nervous system and the recent identification of RAGE as a receptor for amphoterin, which promotes the outgrowth of neuritic processes, support the hypothesis that RAGE is a receptor for ligands other than AGE under normal physiologic conditions (26). In fact, other members of the Ig superfamily have the capacity to bind to more than one biologically relevant ligand in vivo. Podocytes share many structural similarities with telencephalic dendrites, including a complex cytoarchifecture characterized by long cellular processes that are endowed with a highly organized actin cytoskeleton (27). Synaptopodin, a podocyte-specific renal protein that is involved in the organization of the actin cytoskeleton at the junction between the primary processes and the foot processes, is also expressed in telencephalic neurons of developing brain tissue (28). These striking structural similarities between neurons and podocytes raise the question of whether podocyte RAGE may act as a receptor for a currently unidentified renal ligand involved in process formation.
The fact that podocyte RAGE is upregulated in diabetic nephropathy suggests a potential role for the engagement of podocyte RAGE with AGE formed in the underlying GBM. AGE-RAGE interactions in other cellular systems have been reported to promote oxidative stress through modulation of cellular processes (14). Once activated, podocytes are capable of undergoing an oxidative respiratory burst, with release of reactive oxygen species into the GBM; this cellular mechanism has been shown to mediate proteinuria in Heymann nephritis (29). In diabetic nephropathy, it remains to be determined whether ligand-specific activation of podocyte RAGE could promote similar cellular activation, leading to oxidative injury and lipid peroxidation of GBM.
AGE have been reported to form in human tissues in the course of normal aging processes (18). Therefore, the abundant immunostaining of obsolescent glomeruli and arteriosclerotic vessels observed in hypertensive nephrosclerosis and other sclerosing renal conditions is not surprising. These findings support a generalized role for AGE-mediated crosslinking of matrix proteins in the course of irreversible glomerular scarring and progressive arteriosclerosis of intraparenchymal renal vessels.
The generalized accumulation of AGE in obsolescent glomeruli cannot account for the marked deposition of AGE observed in the glomeruli of patients with active lupus nephritis. The formation of AGE in euglycemic inflammatory conditions through enzymatic oxidation of extracellular matrix proteins is a potential explanation for this observation. Lupus nephritis is characterized by neutrophil-mediated tissue injury, including release of reactive oxygen species and proteases. In addition to nonenzymatic mechanisms, CML formation is promoted by enzymatic catalysis by such neutrophil enzymes as myeloperoxidase (30). Activation of the myeloperoxidase-hydrogen peroxide-chloride system converts hydroxy-amino acids into glycolaldehyde, a precursor of CML (30). In lupus nephritis, the formation of AGE appears to be rapid, occurring in the acute phase of glomerular injury before glomerular scarring supervenes. Moreover, the upregulation of podocyte RAGE in this condition suggests a potential role for receptor-dependent cellular effects and correlates with the reported upregulation of RAGE in inflammatory vaculitides (31). The limitations of our study design do not allow us to address the mechanisms mediating this RAGE upregulation or its cellular consequences.
In summary, our findings indicate that CML constitutes a major AGE in renal basement membranes in diabetic nephropathy and is associated with upregulation of podocyte RAGE. The distinctive pattern of mesangial and GBM accumulation of CML observed in diabetic nephropathy differs from the more nonspecific AGE accumulation observed in progressive sclerosing renal conditions characterized by irreversible glomerular scarring and arteriosclerosis. The unexpected finding of AGE in active lupus nephritis suggests that AGE may also play a role in glomerular injury in acute inflammatory glomerulonephritis, probably through oxidative effects on glomerular matrix proteins. These observations in human renal disease provide the foundation for future design of functional studies to address differences in the mechanisms of AGE accumulation in these disorders and the cellular consequences of RAGE upregulation.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-(Carboxymethyl)lysine adducts of proteins are
ligands for receptor for advanced glycation end products that activate cell
signalling pathways and modulate gene expression. J Biol
Chem 274:31740
-31749, 1999-(carboxymethyl)lysine on proteins: A mechanism for
producing advanced glycation end products at sites of inflammation.
J Clin Invest 104:103
-113, 1999[Medline]
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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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K. Kankova, A. Stejskalova, M. Hertlova, and V. Znojil Haplotype analysis of the RAGE gene: identification of a haplotype marker for diabetic nephropathy in type 2 diabetes mellitus Nephrol. Dial. Transplant., June 1, 2005; 20(6): 1093 - 1102. [Abstract] [Full Text] [PDF]
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E. Masson, L. Troncy, D. Ruggiero, N. Wiernsperger, M. Lagarde, and S. E. Bawab a-Series Gangliosides Mediate the Effects of Advanced Glycation End Products on Pericyte and Mesangial Cell Proliferation: A Common Mediator for Retinal and Renal Microangiopathy? Diabetes, January 1, 2005; 54(1): 220 - 227. [Abstract] [Full Text] [PDF]
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M. D. Breyer, E. Bottinger, F. C. Brosius III, T. M. Coffman, R. C. Harris, C. W. Heilig, K. Sharma, and for the AMDCC Mouse Models of Diabetic Nephropathy J. Am. Soc. Nephrol., January 1, 2005; 16(1): 27 - 45. |
