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From the Departments of Pathology, Physiology, and Cellular Biophysics, Surgery and Medicine,*College of Physicians & Surgeons, Columbia University, New York, New York; the Department of Internal Medicine IV,Friedrich-Schiller-University, Jena, Germany; the Department of Medicine I,University of Heidelberg, Germany; and the Department of Molecular Immunology,Division of Tumor Immunology, German Cancer Research Center, Heidelberg, Germany
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Abstract |
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In this context, vascular endothelial growth factor (VEGF) is up-regulated early in diabetes, specifically within podocytes, cells importantly involved in maintenance of glomerular basement membrane structure and integrity.8 In vivo, blockade of VEGF by administration of neutralizing antibodies to diabetic rats abolished hyperfiltration and partially suppressed increased urinary albumin excretion, without affecting control of hyperglycemia.9 Importantly, in addition to its effects on vascular permeability, VEGF mediates recruitment/activation of mononuclear phagocytes (MPs) in a receptor-dependent fashion;10,11 indeed, increased numbers of mononuclear inflammatory cells have been identified in the glomeruli in early experimental diabetes,12,13 as well as in human diabetic kidney.14
Taken together, these studies suggested that activation of distinct VEGF and TGF-ß axes may contribute importantly to the functional and morphological alterations that result in diabetic nephropathy. It was in this context that we speculated a role for receptor for AGE (RAGE). Expression of receptor for AGE (RAGE) is enhanced in human diabetic kidney. Specifically, in the glomerulus, RAGE is expressed especially at the base of podocytes, but not to an appreciable degree in mesangium nor or in the endothelium.15 RAGE, a multiligand member of the immunoglobulin superfamily,16,17 engages ligands implicated in diabetic complications and inflammation, advanced glycation endproducts (AGEs), and members of the S100/calgranulin family.18 Together with these observations, and the emerging role for podocyte activation in the pathogenesis of diabetic nephropathy,13,19-27 it was logical to test the hypothesis that activation of RAGE contributed to increased excretion of urinary albumin and attraction of MPs to diabetic glomeruli driven by enhanced expression of podocyte VEGF and other chemoattractants at early times in diabetes, and expansion of mesangial matrix driven by TGF-ß; events that intersect in the development of diabetes-associated renal insufficiency. To test these concepts, we used the insulin-resistant hyperglycemic db/db mouse, in which diabetes is uniformly established by 8 weeks of age, and the age-dependent decline in renal function and structural abnormalities of the kidney, parallel, at least in part, those observed in human diabetic nephropathy.28,29 In addition, we performed studies in homozygous RAGE null mice and strain-matched controls.30 Diabetes was induced with streptozotocin (stz) and the molecular mediators leading to glomerulosclerosis were examined after 12 weeks of diabetes.
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Materials and Methods |
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Murine podocytes were generously provided by Dr. Paul Klotman (Mt. Sinai School of Medicine, New York, NY) and cultured as described.31,32
Undifferentiated cells were grown on tissue culture dishes in RPMI 1640 containing fetal bovine serum (10%), penicillin/streptomycin (Invitrogen, Carlsbad, CA) and 
-interferon (10 units/ml; Sigma, St. Louis, MO) maintained at 33° in the presence of CO2 (5%). To induce differentiation of the cells into mature podocytes, cells were grown at 37°C on dishes coated with type 1 collagen (0.2 mg/ml; Sigma) in the same medium as above except that -interferon was omitted.
Animal Studies
All animal studies were conducted with the review and approval of the Institutional Animal Care and Use Committee of Columbia University. Male db/db mice (catalog no. 000642) and heterozygote lean non-diabetic mice (catalog no. 100433) were obtained from the Jackson Laboratories (Bar Harbor, ME) and housed in a standard non-pathogen-free environment; water and chow diet were provided ad libitum and mice were exposed to 12 hour light/dark cycles. At age 8 weeks, db/db mice were divided into two groups. The first group received daily intraperitoneal injections of sterile, endotoxin-free murine soluble RAGE,18,33,34
50 µg per day. The second group received equal volumes of vehicle, sterile, endotoxin-free phosphate-buffered saline (PBS), pH 7.4. Mice were sacrificed at age 13 weeks and 27 weeks. Non-diabetic m/db mice were used as controls and treated either with vehicle, PBS or murine sRAGE, 50 µg per day as indicated. At sacrifice, body weight was assessed, and blood and both kidneys were retrieved for analysis. In other studies, male RAGE null mice (129/B6) were used. RAGE null mice are viable and display normal reproductive fitness (30; Liliensiek B, Weigand MA, Bierhaus A, Nicklas W, Kaspar M, Hofer S, Plachky J, Grone HJ, Schmidt AM, Yan SD, Martin E, Stern DM, Hammerling GJ, Nawroth PP, Arnold B, manuscript in preparation). Controls included male 129/B6 animals (Jackson Laboratories). Diabetes was induced in control and RAGE null mice using stz, 65 mg/kg, in citrate buffer for 5 consecutive days at age 8 weeks.33
Control mice received vehicle, citrate buffer. Mice were sacrificed after 12 weeks of diabetes (serum glucose 
250 mg/dl on two separate occasions) or control state.
Analyses
Blood
At sacrifice, blood was obtained from the retro-orbital sinus. Serum creatinine and blood glucose were determined by Analytics (Gaithersburg, MD). The percentage of glycohemoglobin was determined on lysates prepared from red blood cells using a kit from Wallac (Akron, OH) according to the manufacturer’s protocol.
Urine
Twenty-four hour urine collections were obtained from each animal using metabolic cages. Urine albumin and creatinine and plasma creatinine were determined using Albuwell M and creatinine assays from Exocell (Philadelphia, PA) according to the manufacturer’s instructions. Creatinine clearance was determined by the following formula: (urine creatinine in 24 hours) x (volume of urine in 24 hours)/(serum creatinine). Results are expressed as (ml/hour per 100 gram body weight).
Morphometry
Dissected kidneys were fixed in buffered formalin (10%) overnight and then routinely processed for light microscopy. Fixed paraffin-embedded tissues were cut (3 µm thick) and mounted on slides coated with 3-aminopropyltriethoxy silane (Sigma) followed by incubation at 37°C overnight. Light microscopic views after staining with periodic acid Schiff (PAS) (Sigma) were scanned into a computer and the quantification of areas of mesangial matrix and glomerulus was performed using a Zeiss microscope and image analysis system (MediaCybernetics). To calculate mesangial area, only nuclei-free regions were included. Forty glomeruli from each animal were selected at random on the stained sections (20 from the outer region and 20 from the inner region). Thickness of the glomerular basement membrane (GBM) was determined using small pieces of kidney tissue fixed with glutaraldehyde (2.5%) and processed for electron microscopy. Thickness of the GBM was measured in at least five capillaries for each mouse/condition. Morphometry was performed by investigators blinded to the experimental protocol.
Immunohistochemistry
Polyclonal antibodies against RAGE,33,34 S100/calgranulins,18 and affinity-purified antibodies against CML-modified adducts15 were used as previously described. Antibodies to CML-adducts displayed weak immunoreactivity against carboxy(ethyl)lysine (CEL) adducts in ELISA; however, the affinity of the antibody for CML-adducts was >1000 times that for CEL-adducts in these assays. Antibodies to VEGF (Zymed Labs, South San Francisco, CA), monoclonal antibodies to synaptopodin (reactive with the murine epitope) (Maine Biotechnology, Portland, ME), and antibodies against murine Mac-3 (Sigma) were used and immunostaining performed using kits from Vector (Burlingame, CA). In each case, the immunoreaction was visualized using 3,3'-diaminobenzidine (Sigma) and sections were lightly counterstained with hematoxylin. In all cases, the respective nonimmune IgG for each antibody was used at the same concentration as the primary antibody; no specific immunostaining was observed using nonimmune IgG (data not shown).
Immunoblotting
Snap-frozen kidney cortical tissue was homogenized in PBS containing protease inhibitor mixture (Roche Molecular Biochemicals, Indianapolis, IN). Cultured podocytes were washed three times in ice-cold PBS and harvested into lysis buffer (Tris-HCl, 0.05 mol/L (pH 8.0); NaCl, 0.15 mol/L; Triton X, 1.0%; and PMSF, 0.0005 mol/L). Protein concentrations were measured using the Bio-Rad assay system (Bio-Rad Laboratories, Hercules, CA). Equal amounts of protein were subjected to electrophoresis onto Tris-glycine gels (Invitrogen/Novex, Carlsbad, CA) and the contents of the gels were transferred to nitrocellulose membranes (Invitrogen/Novex). Immunoblotting was performed using rabbit anti-RAGE IgG (5 µg/ml), rabbit anti-S100/calgranulin IgG (5 µg/ml), rabbit anti-murine VEGF IgG (1 µg/ml; Santa Cruz Biotechnology, Santa Cruz, CA), or goat anti-murine VCAM-1 IgG (0.4 µg/ml; Santa Cruz Biotechnology). Horseradish peroxidase-conjugated goat anti-rabbit antibody (1:12,000 dilution) (Sigma) was used to identify the sites of primary antibody binding. The enhanced chemiluminescence (ECL) detection system (Amersham-Pharmacia Biotech, Piscataway, NJ) was used to visualize the immunoreaction. Quantitative analysis of the band density was performed using ImageQuant (Molecular Dynamics, Foster City, CA).
Northern Blotting
Northern blots were performed from RNA extracted from renal cortices and hybridized with 32P-labeled cDNA encoding murine transforming growth factor-ß1 (cDNA was generously provided by Dr. F.N. Ziyadeh (University of Pennsylvania)).6
Total RNA was extracted from snap-frozen tissues using Trizol Reagent (Invitrogen). Total RNA (30 µg) was electrophoresed onto an agarose gel (1%), transferred onto a nylon membrane (Schleicher & Schuell, Keene, NH) and cross-linked by ultraviolet light. The cDNA probes were first labeled with Redivue deoxycytidine-5'-[
-32P]triphosphate (
6000 ci/mmol; Amersham Pharmacia Biotech) using random-prime labeling cDNA kit (Stratagene, La Jolla, CA), and the membrane was hybridized with the labeled cDNA probe. After hybridization overnight at 68°C, the blots were washed twice for 15 minutes in 2X standard saline citrate (SSC) containing sodium dodecyl sulphate (SDS) (0.1%) at room temperature, followed by two washes for 15 minutes in SSC (0.1X) and SDS (0.1%) at 60°C. The membranes were autoradiographed at -70°C for up to 5 days. The blots were stripped twice (total of 30 minutes) at 100°C in SSC (0.1X) containing SDS (0.1%) and rehybridized with cDNA fragment encoding ß-actin. Quantitative analysis of the band density was performed using ImageQuant and levels of TGF-ß1 were calculated relative to radioactivity measured for ß-actin.
Statistical Analysis
The mean ± SE (SE) of the mean is reported. Statistical significance (defined as P < 0.05) was determined by analysis of variance. Where indicated, post-hoc analysis was used using Dunnett’s t-test using StatView 4.0 (Abacus Concepts, Inc., Berkeley, CA). Results that did not achieve statistical significance are designated in the figures as "NS."
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Results |
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In contrast to biological settings in which excess accumulation of ligand is accompanied by diminished levels of cellular receptors, expression of RAGE is enhanced in diabetic tissues in a manner overlapping with that of AGEs and S100/calgranulins, such as in atherosclerotic lesions and infected periodontium.33,34
In human diabetic kidney, we previously demonstrated enhanced expression of RAGE in diabetic glomeruli, particularly within podocytes, compared with age-matched euglycemic controls.15
Consistent with the hypothesis that early activation of RAGE in diabetic kidney may modulate processes involved in the development of nephropathy, renal cortical tissue retrieved from the kidneys of db/db mice at age 13 weeks displayed increased RAGE antigen by immunoblotting compared with non-diabetic, m/db mice, of the same age (Figure 1a
; P < 0.05). Immunohistochemistry revealed that the principal site of RAGE expression in the glomerulus of the db/db mouse was the podocyte (Figure 1, b and c)
, as confirmed by co-localization experiments using anti-synaptopodin IgG (data not shown). In contrast, no appreciable staining for RAGE epitopes was detected in mesangium or other cellular structures within the glomerulus. To further demonstrate that podocytes express RAGE, we studied the expression of podocyte RAGE in vitro, using a conditionally immortalized murine podocyte cell line derived from a transgenic mouse expressing a temperature-sensitive SV 40 large T antigen.31,32
Although RAGE antigen was detectable in undifferentiated podocytes, differentiation of these cells on incubation at 37°C in the absence of -interferon resulted in an 4-fold increase in RAGE antigen (Figure 1d
; P < 0.05). Further, we assessed expression of RAGE antigen in non-permeabilized differentiated cultured podocytes by immunohistochemistry. Figure 1e
depicts a single podocyte with arborized processes; RAGE immunoreactivity was evident on the cell surface and appeared to be largely localized to podocyte processes. Although this localization in vitro does not indicate the precise subcellular localization in vivo in the mature podocytes of intact glomeruli, these findings demonstrate that RAGE antigen is detectable by immunoblotting and immunohistochemistry in cultured podocytes.
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, respectively).
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2.3-fold increase in expression of S100/calgranulin antigen in db/db mice compared with m/db controls (Figure 2c
; P < 0.05). S100/calgranulin antigens were principally expressed in inflammatory cells infiltrating the glomerulus and interstitium in db/db mice compared with non-diabetic m/db animals (Figure 2, f and g, and 2, d and e
, respectively). Co-localization studies using anti-Mac 3 IgG indicated that these S100/calgranulin-expressing cells were MPs (data not shown).
Taken together, these observations suggested that RAGE and its ligands, AGEs (CML) and S100/calgranulins, although detectable only at low levels in the absence of diabetes, were present to enhanced degrees in the kidney after 5 weeks of diabetes. As the principal site of increased glomerular RAGE expression was in the podocyte, we tested the hypothesis that engagement of RAGE by AGEs and S100/calgranulins within the glomerulus early in diabetes caused podocyte activation, thereby triggering a series of events leading, ultimately, to altered renal function and glomerulosclerosis. A first test was to determine whether increased expression of VEGF, principally expressed in the podocyte in diabetic kidney,8
was RAGE-dependent. To study this, m/db and db/db mice were treated with murine soluble (s) RAGE, the extracellular ligand-binding domain of the receptor which acts as a decoy to intercept ligand and block access to cell surface RAGE.18,33,34
Mice received once daily intraperitoneal administration of murine sRAGE, 50 µg, or equal volumes of vehicle, phosphate-buffered saline (PBS). Treatment commenced at age 8 weeks, at which time hyperglycemia was documented in all animals, and was continued until the time of sacrifice. At age 13 weeks, renal cortical tissue retrieved from db/db mice displayed VEGF antigen by immunoblotting (Figure 3a)
. Consistent with previous observations in experimental diabetes, the principal site of VEGF expression in diabetic kidney was the podocyte (Figure 3, b and c)
, as demonstrated by studies using anti-synaptopodin IgG (Figure 3d)
. Importantly, treatment of db/db mice treated with sRAGE from age 8 to 13 weeks prevented the increase in expression of VEGF antigen in the kidney at 13 weeks (Figure 3a
; P < 0.01). However, treatment of m/db mice with sRAGE had no effect on levels of VEGF antigen (Figure 3e)
. We extended these studies to cultured podocytes to determine whether activation of RAGE in these cells modulated expression of VEGF. Compared to incubation with irrelevant protein (IgG), incubation of differentiated podocytes with S100B18
resulted in increased expression of VEGF antigen; P < 0.05. That podocyte RAGE was importantly involved in S100B-mediated effects was demonstrated by suppression of VEGF expression in the presence of higher doses of either excess sRAGE (P < 0.05) or anti-RAGE IgG (P < 0.05), but not by lower doses of excess sRAGE or anti-RAGE IgG, nor by nonimmune IgG; P > 0.05 (Figure 3f)
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6.5-fold increase in S100/calgranulin expressing inflammatory cells per glomerulus was noted in db/db mice compared with controls (Figure 3g
; P < 0.01). Immunostaining using anti-Mac 3 IgG confirmed that MPs were the principal cells expressing S100/calgranulin within the glomerulus (data not shown). That RAGE was centrally involved in attracting increased numbers of inflammatory cells to the glomerulus was shown by the significant attenuation in numbers of MPs infiltrating diabetic glomeruli from sRAGE-treated mice compared with those mice receiving PBS (Figure 3g
; P < 0.05). It was likely, however, that VEGF was not the sole trigger in diabetic kidney mediating increased attraction and infiltration of inflammatory cells. As previous studies demonstrated that engagement of RAGE by AGE/CML epitopes or S100/calgranulins resulted in increased expression of vascular cell adhesion molecule-1 (VCAM-1),18,41
we assessed levels of this proinflammatory adhesion molecule in diabetic glomeruli. Immunoblotting revealed that VCAM-1 epitopes in db/db mice treated with sRAGE were significantly lower than those levels observed in vehicle-treated diabetic mice at age 13 weeks (Figure 3h
; P < 0.01). In contrast, treatment of control m/db mice with sRAGE did not affect levels of VCAM-1 antigen (data not shown). These observations support the premise that early up-regulation of RAGE contributes to enhanced influx of inflammatory cells in diabetic kidney, as blockade of RAGE from the time of initial development of hyperglycemia prevented these phenomena. Importantly, in parallel with decreased expression of VEGF and VCAM-1 epitopes, and decreased numbers of infiltrating MPs, levels of RAGE (Figure 1a
; P < 0.05) and S100/calgranulin antigens (Figure 2c
; P < 0.01) were decreased in renal cortical tissue retrieved from sRAGE-treated db/db mice at age 13 weeks compared with vehicle-treated controls. In contrast, treatment of m/db mice with sRAGE did not result in decreased levels of RAGE or S100/calgranulins in m/db animals vs. those treated with PBS at age 13 weeks (data not shown).
These results suggested that blockade of RAGE in db/db mice prevented enhanced expression of factors capable of mediating, at least in part, glomerular hyperpermeability and MP infiltration/activation. An important test of these concepts, however, was the extent to which long-term blockade of RAGE might impact on activation of the TGF-ß axis, a critical mediator of mesangial expansion and glomerulosclerosis in diabetic kidney. To study this, additional groups of db/db mice were treated once daily with sRAGE, or vehicle, PBS, beginning at age 8 weeks and continued until age 27 weeks. In parallel with decreased levels of RAGE (Figure 4a
; P < 0.05) and S100 calgranulin antigens (Figure 4b
; P < 0.05) in renal cortical tissue retrieved from sRAGE-treated db/db mice compared with mice receiving PBS, increased expression of mRNA encoding TGF-ß1 was significantly suppressed in cortical tissue retrieved from sRAGE-treated db/db mice at 27 weeks (Figure 4c
; P < 0.01). We performed PAS-staining of renal cortical tissue retrieved from md/b and db/db animals; consistent with our observations regarding expression of TGF-ß1, although glomerular and mesangial area, as well as mesangial matrix fraction were significantly increased in db/db mice compared with m/db animals (Figure 4, d, e, and f
and Figure 4, h and g
, respectively; P < 0.00001), those db/db mice treated with sRAGE displayed decreased glomerular and mesangial area, in parallel with mesangial matrix fraction compared with db/db mice treated with vehicle (Figure 4, d, e, and f
; and Figure 4, i and h
, respectively; P < 0.00001). In addition, expression of VEGF antigen, although increased in PBS-treated db/db mice compared to m/db controls, was significantly suppressed in diabetic mice treated with sRAGE; P < 0.05 (Figure 5a)
. PBS-treated db/db mice displayed increased thickness of the GBM compared with non-diabetic controls (Figure 5, b, d, and c
, respectively). Importantly, treatment of diabetic mice with sRAGE prevented the increase in GBM thickness at 27 weeks in db/db mice compared with mice treated with vehicle, PBS (Figure 5, b, e, and d
; P < 0.05).
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; P < 0.05). Indeed, the amount of urinary albumin observed in db/db mice treated with sRAGE was not significantly different from that seen in control m/db animals (0.08 ± 0.01 albumin/µg creatinine) (Figure 6a
; P > 0.05). Furthermore, although creatinine clearance was decreased in PBS-treated db/db mice compared with control m/db animals (3.03 ± 0.47 vs. 6.75 ± 0.31 ml/hour/100 x g body weight, respectively; P < 0.001), significantly increased creatinine clearance was observed in db/db mice treated with sRAGE (5.16 ± 0.50 ml/hour/100 x g body weight; P < 0.05 vs. db/db + PBS) (Figure 6b)
. Importantly, the effects of RAGE blockade in db/db mice were independent of changes in body weight, urine volume, serum glucose, or glycosylated hemoglobin (Table 1)
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250 mg/dl were studied; >95% of RAGE null mice and strain-matched controls became diabetic. Mice were sacrificed after 12 weeks of diabetes to identify the early effects of RAGE deletion in the diabetic kidney. Although diabetic strain-matched controls displayed an 1.6-fold increase in kidney/body weight ratio (P < 0.00001) compared to their non-diabetic littermates after 12 weeks of diabetes, no significant increase in this parameter was evident in diabetic RAGE null mice vs. euglycemic mice lacking RAGE; P > 0.05 (Figure 7)
.Consistent with our earlier studies using sRAGE in db/db mice, diabetic RAGE null mice failed to demonstrate increased VEGF antigen in the kidney cortex compared to non-diabetic mice of the same genotype; P > 0.05 (Figure 7b)
. In contrast, strain-matched control mice displayed an 1.9-fold increase in VEGF antigen after 12 weeks of diabetes compared to non-diabetic strain-matched controls; P < 0.05 (Figure 7b)
.
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1.5-fold increase in mRNA for TGF-ß1 in the cortex of the kidney compared to non-diabetic controls after 12 weeks; P < 0.01 (Figure 7c)
. Levels of TGF-ß1 mRNA were not significantly different, however, in diabetic vs. euglycemic RAGE null mice; P > 0.05 (Figure 7c)
. Consistent with these observations, although diabetic strain-matched controls (n = 13) demonstrated an 18% increase in glomerular area, and an 61% increase in mesangial area compared to non-diabetic controls (n = 14); P < 0.001, diabetic RAGE null mice (n = 9) displayed an 5% increase in glomerular area, and a -6% change in mesangial area compared to non-diabetic RAGE null animals (n = 8); P > 0.05.
Furthermore, after 12 weeks of diabetes in wild-type mice (n = 4), GBM thickness was increased 14% compared to non-diabetic controls (n = 4); P < 0.01. In contrast, induction of diabetes in RAGE null mice (n = 4) resulted in a 3% increase in GBM thickness compared to non-diabetic mice lacking RAGE (n = 4); P > 0.05. Importantly, mean levels of blood glucose in diabetic RAGE null mice and diabetic strain-matched controls were not significantly different. Mean levels of blood glucose at sacrifice in diabetic RAGE null vs. diabetic strain-matched controls were 441.4 ± 139.9 and 473.0 ± 76.7 mg/dl, respectively; P > 0.05. Similarly, mean levels of blood glucose did not differ between citrate-treated non-diabetic RAGE null and control mice; 106.7 ± 20.8 and 96.2 ± 18.1 mg/dl, respectively; P > 0.05.
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Discussion |
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illustrates a proposed scheme by which hyperglycemia-mediated generation of AGEs leads to up-regulation and activation of podocyte RAGE; processes linked to enhanced expression of VEGF and its consequences for permeability as well as MP attraction/activation.
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1 and 5(IV) collagen and VEGF. These observations underscore the concept that sustained hyperglycemia may contribute to mechanisms by which podocyte perturbation contributes to diabetic nephropathy. In vivo, however, the complexity of the interplay of the TGF-ß/VEGF axes is demonstrated by the observation that despite blockade of the TGF-ß axis in db/db mice using blocking monoclonal antibodies, levels of mRNA for VEGF were only slightly decreased,7
thus suggesting that at least in part, up-regulation of VEGF may be independent of the action of TGF-ß.
Evidence suggests that, once set in motion, the inexorable increase in proteinuria in diabetes itself is a potent trigger for ongoing glomerular damage and renal dysfunction, as enhanced exposure of tubular cells to urinary protein has been linked to activation of NF-
B, as well as increased expression of chemokines such as RANTES and monocyte chemoattractant protein-1 (MCP-1).49-52
Although these processes are likely mediated, at least in part via TGF-ß, our findings suggest that earlier in the events that typify diabetic nephropathy, activation of RAGE sets the stage for both excess albuminuria as well as glomerulosclerosis and renal insufficiency.
Supportive of an important role for RAGE in induction of pathways leading to tubulointerstitital sclerosis in the diabetic kidney is the recent observation that AGEs mediated epithelial-myofibroblast transdifferentiation via RAGE in cultured renal proximal tubular epithelial cells.53 In addition, Yamamoto and colleagues54 prepared transgenic mice expressing full-length RAGE in endothelial cells (and to some extent in mononuclear phagocytes) to show that when bred with a diabetes-susceptible strain, albuminuria and glomerulosclerosis ensued. Although specific molecular indices of permeability and fibrosis were not examined in the latter study, these observations, together with the present findings, suggest key roles for RAGE in the development of albuminuria and glomerulosclerosis and highlight new insights into early and global mechanisms underlying scarring of the renal cortex in diabetes. Indeed, the recent observation that long-term treatment of normotensive subjects with type 1 diabetes and albuminuria with inhibitors of angiotensin converting enzyme inhibitors or nifedipine did not prevent disease progression, in terms of renal structure, albuminuria, or decline in glomerular filtration rate,55 suggests that fundamental elements of cellular activation that portend advancement of disease are set in motion long before the appearance of albuminuria.56,57
Together with our findings in db/db mice, in which blockade of RAGE was accomplished using soluble receptor, our studies in RAGE null mice support an important role for this molecule in the pathogenesis of diabetic nephropathy. Diabetic RAGE null animals did not display increased expression of VEGF or TGF-ß in the renal cortex. Studies to assess the effects of deletion of RAGE on renal function will be best accomplished by breeding RAGE null animals into the db/db background. These studies, although underway, will require extended periods of time to generate animals sufficiently back-crossed for accurate interpretation of the results. In addition, a limitation of our studies in RAGE null mice is that we did not distinguish the specific cellular contributions of RAGE-bearing macrophages or podocytes (or, perhaps, other cell types) in these processes. Studies are underway to generate transgenic mice bearing dominant-negative RAGE18,37 selectively in cells of mononuclear phagocyte lineage, or in podocytes. As RAGE is primarily expressed by the podocyte in diabetic glomeruli, it will be especially critical to generate the latter group of mice to rigorously test these hypotheses. Thus, in comparison to the studies of Yamamoto,54 targeted expression of RAGE mutants in cells endogenously expressing the receptor in human/murine diabetes (podocytes and MPs) should mimic as closely as possible the naturally occurring setting.
Lastly, important roles for activation of podocytes in other forms of nephropathy have been suggested. For example, in rats with experimentally induced passive Heymann nephritis (PHN) and proteinuria in the glomerulus, podocytes selectively expressed cytochrome b558, an essential component of an NADPH-oxidoreductase enzymatic complex. In PHN, podocytes undergo an oxidative respiratory burst with release of ROS into GBMs. These events were linked to the development of proteinuria,58
as treatment with scavengers of ROS assuaged the development of proteinuria.59,60
These observations have striking parallels to the biology of RAGE. Engagement of RAGE activates NADPH oxidase species in endothelial cells and MPs, thereby triggering signal transduction mechanisms such as p21ras, erk 1/2 MAP kinases, and NF-B in an oxidant-sensitive manner.61-63
It is possible that the podocyte is not an innocent bystander amid distinct derangements in the diabetic glomerulus, but, rather, a key inciting participant, at least in part driven by its enhanced expression of RAGE in a ligand-enriched environment, in the events that lead to scarring and failure of the kidney in diabetes.
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Acknowledgements |
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Footnotes |
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Supported, in part, by the Surgical Research Fund of the College of Physicians & Surgeons, Columbia University, and by grants from Juvenile Diabetes Research Fund International (no. 4200–945) to D.M.S. and A.M.S. T.M.W. is a recipient of a grant from Deutsche Forschungsgemeinschaft (DFG) (We 2450/1–1). P.P.N. was supported by grants from the DFG (Na 138). A.M.S. is a recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research (APP no. 2602).
Thoralf M. Wendt and Nozomu Tanji contributed equally to this work.
Accepted for publication December 19, 2002.
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-(carboxymethyl)lysine is a dominant advanced glycation end product (AGE) antigen in tissue proteins. Biochemistry 1995, 34:10872-10878[Medline]
)-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest 1997, 99:457-468[Medline]
(carboxymethyl)lysine modifications of proteins are ligands for RAGE that activate cell signalling pathways and modulate gene expression. J Biol Chem 1999, 274:31740-31749 B activation. Kidney Int 1998, 53:1608-1615[Medline]
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A. Soro-Paavonen, A. M.D. Watson, J. Li, K. Paavonen, A. Koitka, A. C. Calkin, D. Barit, M. T. Coughlan, B. G. Drew, G. I. Lancaster, et al. Receptor for Advanced Glycation End Products (RAGE) Deficiency Attenuates the Development of Atherosclerosis in Diabetes Diabetes, September 1, 2008; 57(9): 2461 - 2469. [Abstract] [Full Text] [PDF]
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C. Ruster, T. Bondeva, S. Franke, M. Forster, and G. Wolf Advanced glycation end-products induce cell cycle arrest and hypertrophy in podocytes Nephrol. Dial. Transplant., July 1, 2008; 23(7): 2179 - 2191. [Abstract] [Full Text] [PDF]
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L. G. Bucciarelli, R. Ananthakrishnan, Y. C. Hwang, M. Kaneko, F. Song, D. R. Sell, C. Strauch, V. M. Monnier, S. F. Yan, A. M. Schmidt, et al. RAGE and Modulation of Ischemic Injury in the Diabetic Myocardium Diabetes, July 1, 2008; 57(7): 1941 - 1951. [Abstract] [Full Text] [PDF]
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J. M. Forbes, M. T. Coughlan, and M. E. Cooper Oxidative Stress as a Major Culprit in Kidney Disease in Diabetes Diabetes, June 1, 2008; 57(6): 1446 - 1454. [Abstract] [Full Text] [PDF]
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B. I. Hudson, A. M. Carter, E. Harja, A. Z. Kalea, M. Arriero, H. Yang, P. J. Grant, and A. M. Schmidt Identification, classification, and expression of RAGE gene splice variants FASEB J, May 1, 2008; 22(5): 1572 - 1580. [Abstract] [Full Text] [PDF]
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J. Guo, R. Ananthakrishnan, W. Qu, Y. Lu, N. Reiniger, S. Zeng, W. Ma, R. Rosario, S. F. Yan, R. Ramasamy, et al. RAGE Mediates Podocyte Injury in Adriamycin-induced Glomerulosclerosis J. Am. Soc. Nephrol., May 1, 2008; 19(5): 961 - 972. [Abstract] [Full Text] [PDF]
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 J. S. Chang, T. Wendt, W. Qu, L. Kong, Y. S. Zou, A. M. Schmidt, and S.-F. Yan Oxygen Deprivation Triggers Upregulation of Early Growth Response-1 by the Receptor for Advanced Glycation End Products Circ. Res., April 25, 2008; 102(8): 905 - 913. [Abstract] [Full Text] [PDF]
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 S.-Y. Goh and M. E. Cooper The Role of Advanced Glycation End Products in Progression and Complications of Diabetes J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1143 - 1152. [Abstract] [Full Text] [PDF]
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C. Toth, L. L. Rong, C. Yang, J. Martinez, F. Song, N. Ramji, V. Brussee, W. Liu, J. Durand, M. D. Nguyen, et al. Receptor for Advanced Glycation End Products (RAGEs) and Experimental Diabetic Neuropathy Diabetes, April 1, 2008; 57(4): 1002 - 1017. [Abstract] [Full Text] [PDF]
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 A. Aleshin, R. Ananthakrishnan, Q. Li, R. Rosario, Y. Lu, W. Qu, F. Song, S. Bakr, M. Szabolcs, V. D'Agati, et al. RAGE modulates myocardial injury consequent to LAD infarction via impact on JNK and STAT signaling in a murine model Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1823 - H1832. [Abstract] [Full Text] [PDF]
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 N. Origlia, M. Righi, S. Capsoni, A. Cattaneo, F. Fang, D. M. Stern, J. X. Chen, A. M. Schmidt, O. Arancio, S. D. Yan, et al. Receptor for Advanced Glycation End Product-Dependent Activation of p38 Mitogen-Activated Protein Kinase Contributes to Amyloid-{beta}-Mediated Cortical Synaptic Dysfunction J. Neurosci., March 26, 2008; 28(13): 3521 - 3530. [Abstract] [Full Text] [PDF]
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 J. M. Englert, L. E. Hanford, N. Kaminski, J. M. Tobolewski, R. J. Tan, C. L. Fattman, L. Ramsgaard, T. J. Richards, I. Loutaev, P. P. Nawroth, et al. A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis Am. J. Pathol., March 1, 2008; 172(3): 583 - 591. [Abstract] [Full Text] [PDF]
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V. Thallas-Bonke, S. R. Thorpe, M. T. Coughlan, K. Fukami, F. Y.T. Yap, K. C. Sourris, S. A. Penfold, L. A. Bach, M. E. Cooper, and J. M. Forbes Inhibition of NADPH Oxidase Prevents Advanced Glycation End Product-Mediated Damage in Diabetic Nephropathy Through a Protein Kinase C-{alpha}-Dependent Pathway Diabetes, February 1, 2008; 57(2): 460 - 469. [Abstract] [Full Text] [PDF]
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 B. Moser, D. D. Desai, M. P. Downie, Y. Chen, S. F. Yan, K. Herold, A. M. Schmidt, and R. Clynes Receptor for Advanced Glycation End Products Expression on T Cells Contributes to Antigen-Specific Cellular Expansion In Vivo J. Immunol., December 15, 2007; 179(12): 8051 - 8058. [Abstract] [Full Text] [PDF]
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 L. Xia, H. Wang, S. Munk, H. Frecker, H. J. Goldberg, I. G. Fantus, and C. I. Whiteside Reactive oxygen species, PKC-beta1, and PKC-{zeta} mediate high-glucose-induced vascular endothelial growth factor expression in mesangial cells Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1280 - E1288. [Abstract] [Full Text] [PDF]
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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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S. Nakamura, H. Li, A. Adijiang, M. Pischetsrieder, and T. Niwa Pyridoxal phosphate prevents progression of diabetic nephropathy Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2165 - 2174. [Abstract] [Full Text] [PDF]
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S. H. Nasr and V. D. D'Agati Nodular Glomerulosclerosis in the Nondiabetic Smoker J. Am. Soc. Nephrol., July 1, 2007; 18(7): 2032 - 2036. [Abstract] [Full Text] [PDF]
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K.-J. Chen, H.-Y. Peng, C.-L. Cheng, C.-H. Chen, J.-M. Liao, Y.-C. Ho, J.-T. Liou, K.-C. Tung, T.-H. Hsu, and T.-B. Lin Acute unilateral ureteral distension inhibits glutamate-dependent spinal pelvic-urethra reflex potentiation via GABAergic neurotransmission in anesthetized rats Am J Physiol Renal Physiol, March 1, 2007; 292(3): F1007 - F1015. [Abstract] [Full Text] [PDF]
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K. Zen, C. X.-J. Chen, Y.-T. Chen, R. Wilton, and Y. Liu Receptor for Advanced Glycation Endproducts Mediates Neutrophil Migration across Intestinal Epithelium J. Immunol., February 15, 2007; 178(4): 2483 - 2490. [Abstract] [Full Text] [PDF]
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 A. M. Vincent, L. Perrone, K. A. Sullivan, C. Backus, A. M. Sastry, C. Lastoskie, and E. L. Feldman Receptor for Advanced Glycation End Products Activation Injures Primary Sensory Neurons via Oxidative Stress Endocrinology, February 1, 2007; 148(2): 548 - 558. [Abstract] [Full Text] [PDF]
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M. T. Coughlan, V. Thallas-Bonke, J. Pete, D. M. Long, A. Gasser, D. C. K. Tong, M. Arnstein, S. R. Thorpe, M. E. Cooper, and J. M. Forbes Combination Therapy with the Advanced Glycation End Product Cross-Link Breaker, Alagebrium, and Angiotensin Converting Enzyme Inhibitors in Diabetes: Synergy or Redundancy? Endocrinology, February 1, 2007; 148(2): 886 - 895. [Abstract] [Full Text] [PDF]
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 J. Uribarri and K. R. Tuttle Advanced Glycation End Products and Nephrotoxicity of High-Protein Diets Clin. J. Am. Soc. Nephrol., November 1, 2006; 1(6): 1293 - 1299. [Abstract] [Full Text] [PDF]
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 K. G. Raman, P. L. Sappington, R. Yang, R. M. Levy, J. M. Prince, S. Liu, S. K. Watkins, A. M. Schmidt, T. R. Billiar, and M. P. Fink The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock Am J Physiol Gastrointest Liver Physiol, October 1, 2006; 291(4): G556 - G565. [Abstract] [Full Text] [PDF]
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H. J. Zhao, S. Wang, H. Cheng, M.-z. Zhang, T. Takahashi, A. B. Fogo, M. D. Breyer, and R. C. Harris Endothelial Nitric Oxide Synthase Deficiency Produces Accelerated Nephropathy in Diabetic Mice J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2664 - 2669. [Abstract] [Full Text] [PDF]
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K.-M. Myint, Y. Yamamoto, T. Doi, I. Kato, A. Harashima, H. Yonekura, T. Watanabe, H. Shinohara, M. Takeuchi, K. Tsuneyama, et al. RAGE Control of Diabetic Nephropathy in a Mouse Model: Effects of RAGE Gene Disruption and Administration of Low-Molecular Weight Heparin Diabetes, September 1, 2006; 55(9): 2510 - 2522. [Abstract] [Full Text] [PDF]
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 P. M. Humpert, S. Kopf, Z. Djuric, T. Wendt, M. Morcos, P. P. Nawroth, and A. Bierhaus Plasma sRAGE Is Independently Associated With Urinary Albumin Excretion in Type 2 Diabetes Diabetes Care, May 1, 2006; 29(5): 1111 - 1113. [Full Text] [PDF]
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K. Ichinose, Y. Maeshima, Y. Yamamoto, M. Kinomura, K. Hirokoshi, H. Kitayama, Y. Takazawa, H. Sugiyama, Y. Yamasaki, N. Agata, et al. 2-(8-Hydroxy-6-Methoxy-1-Oxo-1H-2-Benzopyran-3-yl) Propionic Acid, an Inhibitor of Angiogenesis, Ameliorates Renal Alterations in Obese Type 2 Diabetic Mice. Diabetes, May 1, 2006; 55(5): 1232 - 1242. [Abstract] [Full Text] [PDF]
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 L. G. Bucciarelli, M. Kaneko, R. Ananthakrishnan, E. Harja, L. K. Lee, Y. C. Hwang, S. Lerner, S. Bakr, Q. Li, Y. Lu, et al. Receptor for Advanced-Glycation End Products: Key Modulator of Myocardial Ischemic Injury Circulation, March 7, 2006; 113(9): 1226 - 1234. [Abstract] [Full Text] [PDF]
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 L. J N Jensen, L. Denner, B. F Schrijvers, R. G Tilton, R. Rasch, and A. Flyvbjerg Renal effects of a neutralising RAGE-antibody in long-term streptozotocin-diabetic mice. J. Endocrinol., March 1, 2006; 188(3): 493 - 501. [Abstract] [Full Text] [PDF]
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L. Gu, S. Hagiwara, Q. Fan, M. Tanimoto, M. Kobata, M. Yamashita, T. Nishitani, T. Gohda, Z. Ni, J. Qian, et al. Role of receptor for advanced glycation end-products and signalling events in advanced glycation end-product-induced monocyte chemoattractant protein-1 expression in differentiated mouse podocytes Nephrol. Dial. Transplant., February 1, 2006; 21(2): 299 - 313. [Abstract] [Full Text] [PDF]
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 P. M. Hall Prevention of Progression in Diabetic Nephropathy Diabetes Spectr, January 1, 2006; 19(1): 18 - 24. [Abstract] [Full Text] [PDF]
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V. Schwenger, C. Morath, A. Salava, K. Amann, Y. Seregin, R. Deppisch, E. Ritz, A. Bierhaus, P. P. Nawroth, and M. Zeier Damage to the Peritoneal Membrane by Glucose Degradation Products Is Mediated by the Receptor for Advanced Glycation End-Products J. Am. Soc. Nephrol., January 1, 2006; 17(1): 199 - 207. [Abstract] [Full Text] [PDF]
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S. Genuth, W. Sun, P. Cleary, D. R. Sell, W. Dahms, J. Malone, W. Sivitz, V. M. Monnier, and for the DCCT Skin Collagen Ancillary Study Group Glycation and Carboxymethyllysine Levels in Skin Collagen Predict the Risk of Future 10-Year Progression of Diabetic Retinopathy and Nephropathy in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications Participants With Type 1 Diabetes Diabetes, November 1, 2005; 54(11): 3103 - 3111. [Abstract] [Full Text] [PDF]
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F. Waanders, W. L. Greven, J. W. Baynes, S. R. Thorpe, A. B. Kramer, R. Nagai, N. Sakata, H. van Goor, and G. Navis Renal accumulation of pentosidine in non-diabetic proteinuria-induced renal damage in rats Nephrol. Dial. Transplant., October 1, 2005; 20(10): 2060 - 2070. [Abstract] [Full Text] [PDF]
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J. M. Bohlender, S. Franke, G. Stein, and G. Wolf Advanced glycation end products and the kidney Am J Physiol Renal Physiol, October 1, 2005; 289(4): F645 - F659. [Abstract] [Full Text] [PDF]
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J. M. Forbes, S. R. Thorpe, V. Thallas-Bonke, J. Pete, M. C. Thomas, E. R. Deemer, S. Bassal, A. El-Osta, D. M. Long, S. Panagiotopoulos, et al. Modulation of Soluble Receptor for Advanced Glycation End Products by Angiotensin-Converting Enzyme-1 Inhibition in Diabetic Nephropathy J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2363 - 2372. [Abstract] [Full Text] [PDF]
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R. Harris Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy: It's All the RAGE J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2251 - 2253. [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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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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G. Wolf, S. Chen, and F. N. Ziyadeh From the Periphery of the Glomerular Capillary Wall Toward the Center of Disease: Podocyte Injury Comes of Age in Diabetic Nephropathy Diabetes, June 1, 2005; 54(6): 1626 - 1634. [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. [Abstract] [Full Text] [PDF]
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 B. F. Schrijvers, A. S. De Vriese, and A. Flyvbjerg From Hyperglycemia to Diabetic Kidney Disease: The Role of Metabolic, Hemodynamic, Intracellular Factors and Growth Factors/Cytokines Endocr. Rev., December 1, 2004; 25(6): 971 - 1010. [Abstract] [Full Text] [PDF]
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J.-L. Wautier and A. M. Schmidt Protein Glycation: A Firm Link to Endothelial Cell Dysfunction Circ. Res., August 6, 2004; 95(3): 233 - 238. [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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 H. Ida, K. Ishibashi, K. Reiser, L. M. Hjelmeland, and J. T. Handa Ultrastructural Aging of the RPE-Bruch's Membrane-Choriocapillaris Complex in the D-Galactose-Treated Mouse Invest. Ophthalmol. Vis. Sci., July 1, 2004; 45(7): 2348 - 2354. [Abstract] [Full Text] [PDF]
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J. M. Forbes, L. T. L. Yee, V. Thallas, M. Lassila, R. Candido, K. A. Jandeleit-Dahm, M. C. Thomas, W. C. Burns, E. K. Deemer, S. R. Thorpe, et al. Advanced Glycation End Product Interventions Reduce Diabetes-Accelerated Atherosclerosis Diabetes, July 1, 2004; 53(7): 1813 - 1823. [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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P. J. Thornalley Glycation, receptor-mediated cell activation and vascular complications of diabetes Diabetes and Vascular Disease Research, May 1, 2004; 1(1): 21 - 22. [PDF]
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A. Flyvbjerg, L. Denner, B. F. Schrijvers, R. G. Tilton, T. H. Mogensen, S. R. Paludan, and R. Rasch Long-Term Renal Effects of a Neutralizing RAGE Antibody in Obese Type 2 Diabetic Mice Diabetes, January 1, 2004; 53(1): 166 - 172. [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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D. T. Bolick, M. E. Hatley, S. Srinivasan, C. C. Hedrick, and J. L. Nadler Lisofylline, a Novel Antiinflammatory Compound, Protects Mesangial Cells from Hyperglycemia- and Angiotensin II-Mediated Extracellular Matrix Deposition Endocrinology, December 1, 2003; 144(12): 5227 - 5231. [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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