Role of Advanced Glycation End Products in Diabetic Nephropathy
Josephine M. Forbes,
Mark E. Cooper,
Matthew D. Oldfield and
Merlin C. Thomas
Danielle Alberti Memorial Centre for Diabetic Complications, Baker Medical Research Institute, Melbourne, Victoria, Australia.
Correspondence to Dr. Merlin Thomas, Danielle Alberti Memorial Centre for Diabetic Complications, Baker Medical Research Institute, P.O. Box 6492, Melbourne, VIC 8008, Australia; Phone: +61-3-85321280; Fax: +61-3-85321480;
ABSTRACT. Nonenzymatic reactions between sugars and the freeamino groups on proteins, lipids, and nucleic acids result inmolecular dysfunction through the formation of advanced glycationend products (AGE). AGE have a wide range of chemical, cellular,and tissue effects through changes in charge, solubility, andconformation that characterize molecular senescence. AGE alsointeract with specific receptors and binding proteins to influencethe expression of growth factors and cytokines, including TGF-1and CTGF, thereby regulating the growth and proliferation ofthe various renal cell types. It seems that many of the pathogenicchanges that occur in diabetic nephropathy may be induced byAGE. Drugs that either inhibit the formation of AGE or breakAGE-induced cross-links have been shown to be renoprotectivein experimental models of diabetic nephropathy. AGE are ableto stimulate directly the production of extracellular matrixand inhibit its degradation. AGE modification of matrix proteinsis also able to disrupt matrix–matrix and matrix–cellinteractions, contributing to their profibrotic action. In addition,AGE significantly interact with the renin-angiotensin system.Recent studies have suggested that angiotensin-converting enzymeinhibitors are able to reduce the accumulation of AGE in diabetes,possibly via the inhibition of oxidative stress. This interactionmay be a particularly important pathway for the developmentof AGE-induced damage, as it also can be attenuated by antioxidanttherapy. In addition to being a consequence of oxidative stress,it is now clear that AGE can promote the generation of reactiveoxygen species. It is likely that therapies that inhibit theformation of AGE will form an important part of future therapyin patients with diabetes, acting synergistically with conventionalapproaches to prevent diabetic renal injury. E-mail: merlin.thomas@baker.edu.au
The growing epidemic of diabetes will ultimately affect morepeople than any other disease in the Western world. More than150 million people currently have diabetes, and twice that numberis at high risk of developing diabetes in the next 5 to 10 yr(1). Despite the clear and present danger of diabetes, knowledgeof the mechanisms by which accumulation of sugars contributesto blindness, cardiovascular disease, and kidney failure remainslimited (2). Among the irreversible changes that occur as aresult of hyperglycemia is the formation of advanced glycationend products (AGE) through a reaction between sugars and thefree amino groups on proteins, lipids, and nucleic acids. Thesechemically heterogeneous compounds are known to have a widerange of chemical, cellular, and tissue effects implicated inthe development and progression of diabetic pathology (Figure 1).In particular is the role of AGE in diabetic nephropathy,in which their importance is demonstrated in studies using inhibitorsof advanced glycation to prevent albuminuria without influencingglycemic control (3). In addition, direct in vivo exposure toAGE is able to generate lesions similar to those seen in diabeticnephropathy (4). This article discusses some of the mechanismsby which AGE may influence renal structure and function.
Diabetic nephropathy is characterized by the accumulation ofextracellular matrix (ECM) protein in the glomerular mesangiumand tubulointerstitium. In its simplest terms, this can be explainedas an imbalance between the synthesis and degradation of ECMcomponents, leading to the pathologic accumulation of collagens,fibronectins, and laminins. AGE are able to influence this balancein a variety ways.
Because of their slow turnover, ECM proteins are especiallysusceptible to AGE modification, resulting in alterations ofboth structure and function. For example, the formation of inter-and intramolecular cross-links after the glycation of collagenleads to structural alterations, including changes in packingdensity (5) and surface charge, manifested by increased stiffness,reduced thermal stability, and resistance to proteolytic digestion(6–8). The reduction in collagen pepsin solubility (asa result of the increased number of acid-stable cross-linksin diabetic collagen) is reflected in a marked increase in acid-insolublecollagen in diabetic tissue (9). Cleavage of AGE-induced cross-linksby agents such as N-phenacylthiazolium bromide and ALT-711 restorescollagen solubility (10,11) associated with a reduction in matrixaccumulation within the kidney (11).
Cell–matrix interactions may also be disrupted by matrixglycation, contributing to changes in cellular adhesion (12),altered cell growth, and loss of the epithelial phenotype. Inaddition, heterotypic interactions between matrix proteins aredisturbed by AGE modifications. The affinity of laminin andfibronectin for type IV collagen and heparan sulfate proteoglycanis decreased after AGE modification (13,14). Glycation alsoinhibits the homotypic interactions required for polymeric self-assemblyof type IV collagen (7) and laminin (14). These changes maybe particularly apparent in the glomerular basement membrane,where the induction of chemical cross-links between amines leadsto an increase in protein permeability (15). Cross-link breakers,however, are able to prevent the development of albuminuriain experimental diabetes (11).
ECM composition may also be substantially altered by AGE. Theexpression of extracellular proteins such as fibronectin andtypes I and IV collagen is increased by AGE in a dose- and time-dependentmanner, in the presence (16) or absence of hyperglycemia (17–19).For example, the glomerular expression of type IV collagen andlaminin is increased after the direct injection of AGE intomice (18). This has been considered to be a direct effect viaAGE-specific receptors involving activation of the JAK/STATsignal transcription pathway (19), leading to the inductionof profibrotic cytokines and growth factors, including TGF-1,PDGF-B, and CTGF (2,20). CTGF (also known as IGF-binding protein-relatedprotein-2) is a potent profibrotic agent and is increased indiabetic nephropathy (21). Inhibitors of advanced glycationsuch as aminoguanidine can prevent increased expression of CTGFin diabetes, associated with a reduction in tissue AGE levelsand the prevention of mesangial expansion (22). In addition,we recently demonstrated that soluble AGE including carboxymethyllysine-containingproteins are able to induce the expression of CTGF and fibronectinproduction in cultured human mesangial cells (22). Similar changesalso have been reported in human dermal fibroblasts, where theAGE-induced upregulation of CTGF is mediated through the receptorfor AGE (RAGE) (23).
Excessive ECM production is also compounded by the increasednumbers of interstitial fibroblasts, myofibroblasts, and infiltratingmacrophages in diabetic nephropathy. Although some of thesecells migrate to the interstitium as a result of chemokinesreleased in response to injury, the transdifferentiation oftubular epithelial cells into a mesenchymal phenotype (tubuloepithelial-mesenchymaltransdifferentiation [TEMT]) has also been implicated in theaccelerated fibrogenesis seen in diabetic nephropathy (24).TEMT is regulated by several growth factors and cytokines, includingTGF-1, fibroblast growth factor, IL-1, and EGF (24). In addition,we have reported that AGE may induce TEMT, potentially contributingto their profibrotic action (20). The mechanism of this actionis the subject of ongoing research, but it seems to be receptormediated, as blockade of the RAGE receptor prevents TEMT, suggestinga crucial role for the AGE/RAGE interaction in cell differentiation.This process seems to be dependent on the activation of TGF-1,as TEMT in response to AGE can be blocked by a neutralizingantibody to TGF-1 (Figure 2) (20). This downstream signalingpathway may be further regulated by intracellular mediatorsof the Smad family, in particular Smad2 or Smad3, which arephosphorylated by the type I TGF- receptor (25). Recent reportsalso suggest that basement membrane composition and integrityis important for the maintenance of epithelial phenotype. Zisberget al. (26) described how type I collagen (known to be upregulatedby AGE and diabetes) promotes TEMT. In addition, inhibitionof assembly of type IV collagen NC1 hexamers (as occurs withcollagen glycation (7)) facilitates EMT in vitro, possibly thoughthe upregulation of TGF-1 in tubular epithelial cells that followsthe disruption of basement membrane architecture (26).
Figure 2. Transdifferentiation of normal rat kidney tubular epithelial (NRK 52E) with a classic cobblestone morphology (A) into elongated myofibroblasts (arrow) in response to AGE (B). This effect can be prevented by the addition of neutralizing ant–TGF-1 antibody (C) (20). Magnification, x400.
At the same time that matrix synthesis is augmented by AGE,the expression and activity of degradative matrix metalloproteinasesare also reduced. Not only are AGE-modified proteins more resistantto enzymatic digestion, but also experimental diabetes is associatedwith a reduction in the matrix-degradative capacity of the kidney(27). This effect is replicated in vitro, with a 45% reductionin the matrix-degrading activity of matrix metalloproteinasessecreted by mesangial cells after growth on glycated matrix(28). In both instances, glycation results not only in a decreasein the expression and activity of matrix metalloproteinasessecreted by mesangial cells but also in the increased expressionand activity of tissue metalloproteinase inhibitors.
Interactions between AGEs and the Renin-Angiotensin System
Overactivity of the intrarenal renin-angiotensin system (RAS)has been strongly implicated in the pathogenesis of diabeticnephropathy, although the source of this activation is not yetestablished (29). AGE significantly interact with the RAS asdemonstrated by the reversal in AGE-induced collagen productionby captopril in vitro, possibly by attenuating RAGE expressionand JAK2/STAT activity (19). We have now demonstrated that invivo angiotensin-converting enzyme (ACE) inhibition attenuatesthe formation and accumulation of AGE in experimental diabetes(30). This may represent a direct effect, as simultaneous incubationof ACE inhibitors with glucose and protein prevents the in vitroformation of AGE, possibly though metal chelation (31). In addition,ACE inhibitors reduce the formation of reactive oxygen species(ROS) associated with diabetic nephropathy and therein reducethe formation of AGE through glycoxidation (2). Treatment withramipril seems to be similar in efficacy to aminoguanidine inreducing glomerular and tubular protein oxidation as assessedby renal nitrotyrosine levels (Figure 3). The source of oxidativestress in the diabetic kidney remains controversial. In vitrostudies suggest a possible role for mitochondrial oxidation(2). In addition, the expression and activity of NAD(P)H oxidasemay represent an important vascular and renal source of oxidativestress in conditions such as diabetes (32,33). Our own studieshave demonstrated an increased expression of the membrane-boundnox-4 subunit in the diabetic kidney (30). However, this doesnot seem to be modified at the gene level by either ACE inhibitionor with the AGE inhibitor aminoguanidine (30). By contrast,increased expression of cytosolic p47phox has been reportedafter 2 wk of streptozocin-induced diabetes, and this NAD(P)Hsubunit could be attenuated by either quinapril or candesartan(34). However, a link between oxidative stress and the productionof AGE is difficult to establish in vivo. Indeed, AGE may generateROS through stimulation of membrane-bound NAD(P)H oxidase viathe RAGE receptor (33). In addition, AGE directly augment theformation of ROS through catalytic sites in their molecularstructure (35).
Figure 3. Aminoguanidine (AG) and ramipril (RAM) reduce increased renal protein expression of nitrotyrosine in experimental diabetes to a similar extent (30). Data are mean ± SEM. *P < 0.01 versus control; P < 0.01 versus diabetes.
AGE result in the expression and activation of a number of transcriptionfactors implicated in the development of diabetic nephropathy,including nuclear factor B (NF-B) and protein kinase C (PKC).This effect may be both direct (through AGE receptors) and indirect,via generation of free oxygen radicals leading to the productionof cytokines, adhesion molecules, and chemokines (Figure 1).These pathways may be synergistic, as depletion of intracellularantioxidants reduces the AGE concentration needed for mesangialcell activation of NF-B (36). In addition, the promoter regionof the RAGE receptor gene contains NF-B binding sites (37),potentially producing a self-perpetuating pathway.
AGE contribute to the release of proinflammatory cytokines andexpression of growth factors and adhesion molecules implicatedin the pathogenesis of the complications of diabetes. Theseinclude VEGF, CTGF, TGF-1, IGF-I, PDGF, TNF-, IL-1, and IL-6(16,20,38). In particular, the induction of TGF-1 seems to bethe key intermediate step for many of the AGE-mediated effectson cell growth and matrix homeostasis as noted earlier (20).In addition, inhibitors of advanced glycation reduce the overproductionof TGF-1 in diabetic animals, independent of glycemic status(16). The transcriptional upregulation of TGF-1 in diabetesseems to be mediated via PKC-dependent pathways for which AGEare a potent stimulus. Moreover, renoprotective treatment withinhibitors of AGE has been shown to attenuate renal PKC overexpressionin diabetic rats (38). Some studies have also suggested an importantrole for oxidative stress in the AGE-induced TGF-1 transcription.This is illustrated by the finding that antioxidants are ableto prevent the upregulation of TGF-1 after exposure to AGE (36).However, the failure of antioxidant therapy to prevent end-organinjury in the diabetic cohort of the Heart Outcomes PreventionEvaluation (HOPE) study casts some doubt on the pathologic significanceof oxidative stress in progressive diabetic renal injury (39,40).
AGE accumulation in the glomerular and tubulointerstitial compartmentsand structural alterations of ECM proteins correlate with theseverity of diabetic nephropathy. There is now strong evidencethat AGE are directly pathogenic. Interventions to reduce renalAGE accumulation seem to be renoprotective in the context ofdiabetes. However, advanced glycation is only one pathway bywhich renal injury may be induced in diabetes. It seems likelythat an interaction of metabolic and hemodynamic factors compoundthe deleterious effects of the diabetic milieu and reduce thethreshold for injury via common mechanisms (40). Therapies thattarget multiple pathways may indeed be more successful thanthose that target one alone. It remains to be determined whethera combination of hemodynamic and metabolic pathways is moreeffective than any individual therapy in preventing diabetes-associatedrenal injury.
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Top
Abstract
Introduction
1 and CTGF, thereby regulating the growth and proliferation of the various renal cell types. It seems that many of the pathogenic changes that occur in diabetic nephropathy may be induced by AGE. Drugs that either inhibit the formation of AGE or break AGE-induced cross-links have been shown to be renoprotective in experimental models of diabetic nephropathy. AGE are able to stimulate directly the production of extracellular matrix and inhibit its degradation. AGE modification of matrix proteins is also able to disrupt matrix–matrix and matrix–cell interactions, contributing to their profibrotic action. In addition, AGE significantly interact with the renin-angiotensin system. Recent studies have suggested that angiotensin-converting enzyme inhibitors are able to reduce the accumulation of AGE in diabetes, possibly via the inhibition of oxidative stress. This interaction may be a particularly important pathway for the development of AGE-induced damage, as it also can be attenuated by antioxidant therapy. In addition to being a consequence of oxidative stress, it is now clear that AGE can promote the generation of reactive oxygen species. It is likely that therapies that inhibit the formation of AGE will form an important part of future therapy in patients with diabetes, acting synergistically with conventional approaches to prevent diabetic renal injury. E-mail: merlin.thomas@baker.edu.au 
B (NF-
, IL-1
P < 0.01 versus diabetes.