Extracellular Matrix Metabolism in Diabetic Nephropathy
Roger M. Mason and
Nadia Abdel Wahab
Cell and Molecular Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Imperial College London, London, UK.
Correspondence to Professor Roger M. Mason, Cell and Molecular Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Imperial College London, Exhibition Road, London, SW7 2AZ, UK. Phone: 44-20-7594-3019; Fax: 44-20-7594-3015;
ABSTRACT. Diabetic nephropathy is characterized by excessivedeposition of extracellular matrix proteins in the mesangiumand basement membrane of the glomerulus and in the renal tubulointerstitium.This review summarizes the main changes in protein compositionof the glomerular mesangium and basement membrane and the evidencethat, in the mesangium, these are initiated by changes in glucosemetabolism and the formation of advanced glycation end products.Both processes generate reactive oxygen species (ROS). The reviewincludes discussion of how ROS may activate intracellular signalingpathways leading to the activation of redox-sensitive transcriptionfactors. This in turn leads to change in the expression of genesencoding extracellular matrix proteins and the protease systemsresponsible for their turnover. E-mail: roger.mason@imperial.ac.uk
Diabetic Nephropathy: The Magnitude of the Problem
Diabetes mellitus has recently assumed epidemic proportions,partly due to the 2 to 5% increase in the incidence of type1 diabetes in children, but especially due to the global increasein type 2 diabetes (1). Currently as many as 4% of obese adolescentsin the United States may have silent type 2 diabetes (2). Secondarymicrovascular complications, including nephropathy, developsome years after the onset of diabetes. Genetic background islikely to be important in determining susceptibility to diabeticnephropathy (DN) (3), but exposure of tissues to chronic hyperglycaemiais the main initiating factor (4,5). The prevalence of nephropathyvaries according to geographical location, type of diabetes,and the length of time since diagnosis. Microalbuminuria isa sign of early DN, while macroalbuminuria indicates progression(6). While there is a similar prevalence of microalbuminuriain diabetic patients in the Unite States and Europe (22 and25%), the prevalence of macroalbuminuria is higher in the UnitedStates (27% compared with 12%) (7). In a Japanese study, 44%of type 2 diabetic patients developed DN by 30 yr after diagnosisbut only 20% of type 1 patients did so (8). Despite these regionalvariations, the prevalence of DN is predicted to increase inthe decades ahead (9,10). DN is a major cause of end-stage renaldisease (11), and new therapeutic approaches are required tolimit its development. Evolution of these will depend on understandingthe molecular mechanisms driving glomerulosclerosis and interstitialfibrosis in DN. This review surveys current understanding inthis area.
Similar ultrastructural changes occur in glomeruli in types1 and 2 diabetes (12,13). The glomerular basement membrane increasesin thickness, and the extracellular matrix of the mesangiumexpands. The basement membrane changes, accompanied by glomerularhyperfiltration, and increased glomerular hydrostatic pressurelead to microalbuminuria. However, the mesangial changes appearto be the main cause of declining renal function in DN (14).As the mesangial matrix expands, it impinges on glomerular capillaries,reducing the surface available for filtration and narrowingor occluding the lumen. Declining glomerular function correlateswell with the extent of these changes in both types of diabetes(15,16), although there appears to be more heterogeneity inthese structural changes in type 2 (17).
Tubulointerstitial fibrosis occurs in DN, in addition to glomerulosclerosis,but it has been much less well studied. However, decreased creatinineclearance correlates with the interstitial expansion as wellas with mesangial expansion (18) and survival rates diminishif interstitial fibrosis is present (19). In this respect, diabeticnephropathy is similar to other renal disorders in which progressiveloss of renal function correlates with advancing interstitialfibrosis (20). Interstitial fibrosis in DN may be initiatedby the same factors as glomerular fibrosis, as well as beinginfluenced subsequently by factors originating in the glomerulus(21).
Expansion of the mesangial matrix and thickening of the glomerularbasement membrane (GBM) in DN could be due to either increasedaccumulation of proteins that are normally present in thesestructures or to deposition of proteins that are not presentin normal tissue or to both. Table 1 summarizes some of themany reports of matrix proteins that are present in the mesangiumand GBM in DN. It is clear that some mesangial proteins suchas collagen I and III are only expressed in the late stagesof glomerulosclerosis. They are associated with the developmentof Kimmelstiel-Wilson nodules rather than with the diffuse expansionof the mesangial matrix, which occurs in the early and moderatelyadvanced stages of the disease. Other proteins such as fibronectinare present in the normal mesangium but increase in the expandingmesangium.
Table 1. Glomerular matrix proteins in diabetic nephropathy (DN)
Differences between quantitative electron microscopy-immunogoldmeasurements of the levels of matrix proteins in the mesangiumand GBM and data obtained by immunohistochemical and immunofluorescencestudies complicates the interpretation of which proteins areresponsible for expansion or thickening. Thus an immunogoldanalysis showed decreased type VI collagen per unit area ofthe mesangium and decreased total type VI per glomerulus mesangialmatrix in "fast track" DN patients with diffuse mesangial expansioncompared with controls (30). In contrast, immunohistochemicaland immunofluorescence investigations concluded that increasedtype VI deposition occurs (25,32). Such differences could bedue to the immunogold study focusing on an earlier stage ofthe disease and on type 1 patients, whereas the light microscopystudies were largely concerned with late-stage DN in type 2diabetic patients. Nevertheless, the quantitative study provokesthe question as to precisely which matrix proteins are responsiblefor diffuse mesangial expansion and whether there may be subtledifferences in the molecular changes in type 1 and 2 diabetes.Only further quantitative investigations on well-defined cohortsof patients will provide definitive answers.
The main components of the normal GBM are type IV collagen,laminin, entactin, and proteoglycans. GBM type IV collagen iscomprised predominantly of 3, 4, and 5 chains (39,40). Table 1summarizes some of the changes that occur during thickeningof the GBM in DN. The loss of heparan sulfate proteoglycanswith disease progression is associated with proteinuria (44,46),the glycosaminoglycan chains normally forming an anionic chargebarrier to protein diffusion across the GBM (49).
Genetically determined diabetes mellitus occurs in db/db mice(a model for type 2), and type 1 diabetes can be induced inmice and rats with streptozotocin (STZ). These models developnephropathy with changes in glomerular extracellular proteinsthat appear to be similar to those in human DN. There is increasedglomerular expression and accumulation of type IV collagen andfibronectin (50–53), while the relative content of heparansulfate proteoglycan content is reduced (50). As in human DN,hyperglycemia is likely to be the main factor initiating thesechanges.
Studies using in situ hybridization to detect specific mRNAsindicate that increased expression of several different genesencoding matrix proteins is likely to be responsible, in part,for their accumulation in glomerular matrices in DN in bothhumans (24,26,54) and in animal models (51,53). However, glomerularmatrix proteins also normally undergo metabolic turnover, beingdegraded primarily by matrix metalloproteinases (MMP) (55).Any decrease in turnover would promote excessive matrix accumulation,and there is evidence that this too occurs in DN. GlomerularmRNA levels for MMP2 (gelatinase A) and MMP3 (stromelysin) decreasein human DN (54,56), while in STZ-induced diabetes in rats,MMP9 (gelatinase B) mRNA and activity fell and tissue inhibitorof metalloproteinase-1 (TIMP1) mRNA increased (57,58). In thismodel, MMP3 mRNA levels increased (58). Nevertheless, MMP3 activityand overall glomerular MMP activity decreased (58,59). Activityof MMP is controlled at multiple steps, including their levelof synthesis as inactive proenzymes, activation of the proenzymesand, subsequently, inhibition of active enzymes by binding toTIMP (60). Plasmin cleaves and activates MMP proenzymes, whilemembrane type metalloproteinase-1 (MT1-MMP) is involved specificallyin activating MMP2. In vitro evidence indicates that high-glucoseconditions reduce plasmin activity by upregulating expressionof plasminogen activator inhibitor (PAI-1) in mesangial cells(MC) (61,62) while suppressing expression of MT1-MMP (63). Thus,overall, turnover of mesangial matrix proteins in DN is likelyto be compromised by decreased MMP expression, decreased levelsof proenzyme activation, and increased expression of the MMPinhibitor, TIMP1.
Mesangial Cell Responses to Hyperglycemic Conditions In Vitro
Many in vitro investigations have exposed MC to high concentrationsof glucose, or to albumin-Amadori adducts, or to albumin-advancedglycation end products (AGE) to mimic the conditions they experiencein vivo. The formation of Amadori-protein adducts and AGE-proteinsis initiated in vivo by the non-enzymatic interaction of proteinamino-groups with glucose (64) or with metabolites of glucosesuch as methylglyoxal (65). Increased levels of glycated proteinsoccur in the plasma, renal, and other tissues in diabetes (66–68).MC respond to culture medium containing high glucose concentrationor glycated-albumin by upregulating the expression of many ofthe matrix proteins that accumulate in the mesangium in DN,and by changes in the expression of MMP and proteinase inhibitors.Some examples are shown in Table 2. It is apparent that bothinduce similar effects, even though those of glucose dependon its metabolism, following uptake into the cell by facilitativeglucose transporters (75), while glycated-proteins interactwith cell surface receptors (76,77).
Table 2. Mesangial cell protein expression in vitro in response to hyperglycemic stimulia
As well as being exposed to circulating glycated-proteins, mesangialand other cells are likely to be affected by the function ofintracellular proteins being compromised by AGE formation andby cellular interactions with insoluble glycated matrix proteins.The latter lead to some of the same effects in vitro as areinduced by high glucose; for example, increased expression ofMMP2 and TIMP1 and decreased expression of MT1-MMP (78). Glycationof type IV collagen and laminin affects their structure andassembly into polymers (79–81). Formation of advancedglycation end products of collagen IV or glomerular basementmembrane also markedly inhibits their susceptibility to cleavageby MMP3 and MMP9 (82), impeding their turnover.
Other glomerular cells also respond to high-glucose conditionsor to glycated-albumin in vitro. For example, glomerular visceralepithelial cells exposed to high glucose have been reportedto upregulate expression of transforming growth factor- (TGF-)and fibronectin (83) and TGF- type II receptor (84), while glycated-albuminstimulates the production of collagen IV and fibronectin inglomerular endothelial cells (85).
The response of MC to hyperglycemia is clearly complex, anddifferential gene screening techniques have proved useful forunderstanding more fully the changes in gene expression thatoccur after exposure to high glucose. mRNA differential displayindicated that a large number of genes undergo changes in expressionafter exposure of human MC to 30 mM D-glucose (86), and suppressionsubtraction hybridization (SSH) subsequently identified 70 knowngenes that were induced under these conditions, a further 26showing similarity to expressed sequence tags (EST) and 100cDNAs representing genes that are downregulated (87,88).
Differential screening of MC exposed to high glucose revealedincreased expression of genes that, potentially, play a rolein the development of glomerulosclerosis, including connectivetissue growth factor (CTGF) (87,89). Its role in promoting thesynthesis of mesangial matrix proteins is discussed below. However,expression screening also indicated that mRNA for both subunitsof the fibronectin receptor (5,1 integrin) is increased in high-glucoseconditions (N.A. Wahab and R.M. Mason, unpublished work). Furtherexperiments demonstrated that TGF-, acting at least in partthrough a CTGF-dependent pathway, increases the number of 51receptors on the cell surface and their occupation by ligand(90). This promotes increased deposition of insoluble fibronectinmatrix around the cells, a process that can be inhibited byanti-1-neutralizing antibody (90). This mechanism may representone mechanism for the development of fibrosis in the mesangiumin DN. It is also conceivable that an increased number of mesangialcell surface 51 integrin sites ligated by fibronectin may modulatecell behavior by an outside-in signaling mechanism. MC culturedin three-dimensional collagen gels show fibronectin-dependentactivation of phosphsatidylinositol-4-phosphate 5-kinase byoutside-in signaling (91). Fibronectin signaling stimulatesprotein kinase C (PKC) translocation to the cell membrane inCHO cells (92) and induces hypertrophy of cardiac myocytes,accompanied by increased transcription of the brain natriureticpeptide gene (93).
Changes in Intermediary Metabolism in Response to Hyperglycemia
A high plasma glucose concentration leads to elevated intracellularglucose levels in cells such as MC in which uptake is not regulatedby insulin. The increased uptake in MC is probably achievedby increased expression of GLUT1 in response to high glucose.GLUT 1 is a high affinity, low capacity facilitative glucosetransporter which is near saturated at normal physiologic concentrationsof glucose (75). Glucose is normally metabolized through glycolysisand the tricarboxylic acid cycle, generating CO2 and the reducedcoenzymes NADH and FADH2. The latter reoxidize by donating electronsto the respiratory chain (electron transport chain) in the innermitochondrial membrane, where they reduce molecular oxygen toform water. Passage of electrons through the chain results ina proton gradient across the membrane which drives oxidativephosphorylation, producing ATP. High intracellular glucose levelsgenerate increased production of several glucose metaboliteswhich are normally present in only low concentration and theglucose and three of these products stimulate activity of fourother pathways, and actions downstream of them. Thus (1) diacylglycerol(DAG), derived from the glycolytic intermediate dihydroxacetonephosphate (DHAP), activates several isoforms of PKC; (2) dicarbonylmetabolites such as glyoxal and methylglyoxal, derived fromglucose and the glycolytic intermediates DHAP and glyceraldehyde-3-phosphate(G3P), initiate AGE formation; (3) fructose-6-phosphate, a glycolyticintermediate, when present in raised concentration, enters andincreases flux through the hexosamine biosynthetic pathway,generating UDP-N-acetylglucosamine. This promotes glycosylationof Sp1 and possibly of other transcription factors, modulatingtheir activity; (4) glucose itself, which when present in raisedconcentration enters the aldose reductase pathway and is convertedto sorbitol. This utilizes the reduced coenzyme NADPH. The resultingNADP is converted back to NADPH using the cell’s antioxidant,reduced glutathione, depleting the latter and increasing cellsusceptibility to reactive oxygen species (ROS). The detailsof activation of these four pathways in high glucose have beenreviewed extensively recently (94,95). Increased productionof NADH and FADH2 and donation of electrons from them to therespiratory chain increases the proton gradient across the innermitochondrial membrane, which inhibits electron transport atcomplex III of the chain. Electrons carried by coenzyme Q, whichnormally pass to complex III, then generate intracellular ROSby reducing O2 to superoxide ion O2- (94). This also inhibitsactivity of the glycolytic enzyme glyceraldehyde-3-phosphatedehydrogenase (96), potentially raising the level of metabolicintermediates between glucose and G3P and their entry into thefour pathways. The formation of AGE also generates extracellularROS due to the autooxidation of glucose (97). This may leadto the activation of latent TGF (L-TGF) (98). ExtracellularAGE also bind to the cell surface receptor, RAGE, which is expressedin various renal cell types (76,77). This initiates intracellularROS production (99).
Support for the involvement of ROS and AGE in inducing DN invivo comes from studies on the effect of various inhibitorson animal models. Thus, overexpression of Cu2+/Zn2+ superoxidedismutase in mice protects them from glomerular injury afterinduction of diabetes with STZ (100). Inhibitors of non-enzymaticglycation of proteins attenuate glomerular and interstitialdamage in db/db mice (101–106) and in diabetic transgenicmice overexpressing RAGE (a receptor for AGE), which otherwisedevelop advanced glomerulosclerosis (107). Likewise, inhibitionof PKC attenuates mesangial expansion in db/db mice (52) andglomerular dysfunction in the STZ rat (108). Sorbinil, an inhibitorof the aldose reductase pathway, reduced GBM width in STZ ratson low-protein diets but not in those on higher-protein diets(109). However, definitive evidence of the efficacy of antioxidants,or inhibitors of AGE-formation, PKC activation, or of the aldosereductase pathways, in attenuating the development of DN inhumans is still awaited (95).
To date, there are no in vivo studies on the effect of blockingthe hexosamine biosynthetic pathway on glomerular function indiabetic models. However, inhibition of glutamine:fructose-6-phosphate-amidotransferase(GFAT), the rate-limiting enzyme of the pathway, inhibits high-glucose–inducedTGF- production (110) and NF-B-dependent promoter activation(111), two key events in the response to high glucose (see below).Overexpression of GFAT activates the PAI-1 promoter (112), anotherkey event.
Growth Factors and Hormones Affecting Matrix Protein Expression in DN
In vitro and in vivo studies have shown that several differentgrowth factors are upregulated in DN, and the signaling pathwaysthese activate ultimately regulate transcription factors affectingglomerular ECM accumulation. The principle factors and hormonesinvolved are angiotensin II (AngII), TGF-, CTGF, platelet derivedgrowth factor (PDGF), growth hormone (GH), and insulin-likegrowth factors (IGF).
Angiotensin II.
Activation of the renal renin-angiotensin system (RAS) and itsinvolvement in the pathogenesis of DN is indicated by severalstudies that showed that both angiotensin-converting enzyme(ACE) inhibitors and angiotensin-receptor-I antagonists attenuateDN (11,113–114). The entire RAS is present in the kidney(115). In vitro studies show increased angiotensin expressionin mesangial and tubular cells in response to glucose (116,117).This response was shown to be mediated, at least in part, byROS and subsequent activation of p38 MAPK in tubular cells (118).AngII, the active octapeptide derived from angiotensinogen,also stimulates ROS generation in vascular smooth muscle cells(119) and MC (120). The ROS signaling pathway activates NF-B,which mediates further angiotensinogen expression, so ROS generationcould be part of a positive feedback loop (121), perpetuatingactivity of the RAS in DN. Increased AngII is also generatedin hypertension, a disorder that frequently accompanies diabetesand accelerates progression of DN (122). Several intrarenalhemodynamic changes, including glomerular capillary hypertension,occur in early experimental diabetes. This and the subsequentdevelopment of albuminuria and glomerular structural changesis attenuated by ACE inhibition (123), demonstrating the importanceof hemodynamic factors in the pathogenesis of DN. It is noteworthythat intraglomerular hypertension can occur in diabetes evenin the absence of systemic hypertension (124). Although AngIIis associated with both systemic and renal hemodynamic effects,it also has direct nonhemodynamic effects on glomerular cells,particularly MC. AngII has been shown to increase ECM accumulationby MC, primarily via stimulation of TGF- expression (53,115,125–127).The mechanism by which AngII transactivates TGF- was found tobe similar to that for hyperglycemia. Both transactivate thegrowth factor gene through two AP-1 regulatory elements (128–130).This activation appears to be PKC- and p38 MAPK-dependent (129,130).
Transforming Growth Factor-.
Numerous studies indicate that hyperglycemia induces an increasein TGF- expression on both the mRNA and protein levels in experimentaland human diabetes (51,127,130–132) as well as in culturedMC (71,133,134). TGF- appears to be involved in both the earlyand later stages of DN. In STZ-diabetic rats, renal TGF- expressionincreased markedly as early as 24 h after the onset of hyperglycemia(135). A similar increase was also reported in the non-obesediabetic (NOD) mouse (136,137) and in the diabetic BB rat (136).Sustained elevated expression of TGF- occurs in STZ-diabeticrats with diabetes of 24-wk duration (138) and in the kidneyof 16-wk-old diabetic db/db mice (139). All TGF- isoforms, TGF-1,2, and 3, and the TGF- type II receptor were reported to beelevated in experimental diabetes (139–141). Increasedrenal production of TGF- in patients with diabetes and DN isalso well documented (127,142,143). In addition, many in vitrostudies have shown that TGF- expression is increased in variousrenal cells cultured under high-glucose conditions or with AGE(71,73,143–145).
It is now clear that TGF- is the key cytokine mediating theproduction of different ECM proteins in MC, epithelial cells,renal interstitial cells, and fibroblasts (71,133,144,146–151).TGF- also influences matrix-degrading enzymes by inhibitingthe synthesis of collagenases and stimulating the productionof TIMP and PAI-1 (149,150,152–154). TGF- can also influencelocal matrix deposition by upregulating different ECM receptors(90,150).
Although the main signaling pathway of TGF- is the Smad pathway(155) and is activated in the STZ-diabetic mouse model (156),TGF- also activates other pathways such as the MAPK (ERK, SAPK/JNK,and p38 MAPK) (157,158). TGF- induces PKA activation in MC bya mechanism involving the degradation of the inhibitory peptideof PKA (PKI) (159).
Connective Tissue Growth Factor.
CTGF is another prosclerotic cytokine and has also been shownto be involved in both the early and later stages of DN. Itsexpression is increased in experimental diabetic glomerulosclerosis(160,161). Elevated CTGF levels in glomeruli of NOD mice appearto correlate with the duration of diabetes (89). Elevated CTGFexpression was also detected in human DN (89,162,163). In vitrostudies have shown that CTGF is induced in renal cells by bothhigh glucose and AGE (87,89,160), as well as ROS (164), whichthey generate. The induction of CTGF in MC by hyperglycemiaseems to be partly TGF-–dependent and partly PKC-dependent(165,166).
CTGF is one of the TGF--inducible immediate early genes (167)and is induced in cultured MC by TGF- (168–170). TGF-induces CTGF gene expression via Smad binding elements (SBE)and a unique TGF- response element in the CTGF promoter (170–172).The induction of CTGF by TGF- seems to be PKC- and MAPK-dependent(170).
Emerging evidence from in vitro studies of renal cells, includingMC, indicates that CTGF is a crucial mediator for TGF--stimulatedmatrix protein expression. CTGF has been shown to mediate TGF--inducedincreases in fibronectin (89,168,173), collagen type I (174–176),and the fibronectin receptor (51 integrin) (90).
Other ECM proteins that have been reported to be induced byCTGF in different renal cells include collagens I, III, andIV, tenascin, and thrombospondin-1 (TSP-1) (87,177,178). Inductionof FN by CTGF in MC appears to be mediated by the activationof MAPK and PKB pathways (179). Recent work in our laboratoryhas shown that MC exposed to CTGF downregulate expression ofSmad7 (Wahab and Mason, unpublished work). Smad7 is an inhibitorof the Smad signaling pathway (155); we therefore propose thatCTGF promotes increased TGF- signaling through this pathwaydue to decreased availability of Smad7. We hypothesize thatthis accounts, at least in part, for CTGF’s profibroticactivity.
Platelet-Derived Growth Factor.
Glomerular mRNA levels for PDGF-B chain are enhanced fivefoldin experimental diabetes (106). PDGF has been reported to mediateboth high glucose– and AGE-dependent induction of typeIII collagen in cultured rat MC. However, its effect seems tobe through augmenting the production of TGF- (180,181). Anti-PDGFantibodies also attenuated the increased production of typeIV collagen in MC exposed to AGE, again suggesting that PDGFacts as an intermediate factor (182).
Growth Hormone and Insulin-Like Growth Factors.
Classically, GH secreted from the pituitary induces the synthesisof IGF in various tissues through activation of the GH receptor(GHR). Two lines of evidence implicate GH in the pathogenesisof glomerular fibrosis in experimental diabetes. One is therenoprotective effect of long-acting somatostatin analogs andGHR antagonists (183). The other is the failure of STZ-treatedmice, which are either transgenic for a mutated GH, which isan antagonist of native GH, or in which the GHR/binding proteingene has been knocked out, to develop glomerular lesions (184–186).Transgenic mice that overexpress GH or GH releasing factor developglomerulosclerosis, but those expressing an IGF-1 transgenehave morphologically normal, though enlarged, glomeruli (187).Overall the evidence favors GH having a direct effect in thepathogenesis of glomerulosclerosis, independent of IGF. PlasmaGH levels are raised in type I diabetic patients with poor glycemiccontrol, while the concentration of IGF-I is low and that ofIGF binding protein 1 (IGFBP1), a modulator of its activity,is raised (e.g., 188). Intraportal insulin deficiency decreaseshepatic IGF-I synthesis and increases production of IGFBP intype I diabetes, while hypersecretion of GH occurs as a resultof lowered negative feedback of IGF-1 on secretion (189).
How GH induces glomerulosclerosis directly is not known, butmRNA for GHR has been detected in MC and they respond to thehormone in vitro by upregulating iNOS transcripts and nitricoxide production (190). However, iNOS knockout mice show moreadvanced mesangial expansion, increased GBM staining for collagenIV, and tubulointerstitial fibrosis, after induction of diabeteswith STZ than do controls, suggesting a protective effect forNO in vivo with respect to matrix deposition (191). On bindingits cellular receptor, GH activates the JAK/STAT, MAPK, andP13K signaling pathways (192), so it may potentially regulatethe transcription of a number of genes.
IGF-I may be expressed in the kidney independently of GH. MCcultured on glycated-albumin increase IGF-I production (193),and the growth factor directly stimulates synthesis of laminin,fibronectin, proteoglycan, and type IV collagen in these cells(194–196). IGF-I and IGF-BP species have also been reportedto increase in the kidney in the early stages of experimentalDN (197–200), while the expression level of IGF-IR risesin a later phase (201). IGF-I and IGF-II signal through twospecific receptors, IGF-IR and IGFII/mannose-6-phosphate receptor(IGF-II/man-6-PR) (202,203). IGF-I activates the phosphatidylinositol-3-kinase(PI3K) and ERK1/2 MAPK pathways (196,204). It has also beenshown to stimulate NF-B (205). In the presence of high glucose,IGF increased IGF-I-stimulated insulin receptor substrate-1/2phosphorylation and AP-1 transcriptional activity, while decreasingIGFBP-2 expression (204). Thus, despite lower circulating levelsof IGF-I in diabetes, locally produced growth factor may influenceMC in vivo. MC from diabetic NOD mice secrete increased amountsof IGF-I, and this probably contributes to the increased ECMaccumulation, largely through an IGF-I-mediated reduction inMMP2 activity (206).
ROS and the Activation of Pathways Stimulating Matrix Accumulation
Although further in vitro and in vivo confirmatory studies arerequired, current data strongly suggest that intracellular ROS,from either AGE-RAGE interaction or glucose metabolism (94,207),have a direct role in overproduction of ECM proteins and thatthis can be counteracted by antioxidants (208). It has beenshown that ROS activate the PKC, MAPK, and JAK-STAT pathways(209–212), which lead to the activation of redox-sensitivetranscription factors including NF-B, AP-1 (Fos and Jun proteins),STAT, and Egr-1 (99,213–215). These enhance the transactivationof genes coding for cytokines such as TGF- and CTGF that upregulateECM protein expression (164,216–217).
Thombospondin-1.
TSP-1 is one of five isoforms of thrombospondin and is synthesizedand secreted by a variety of renal cells, including MC (86,218).Exposure to high glucose upregulates TSP-1 expression in MC(86), and increased levels of glycoprotein occur in the glomeruliin diabetic animals (219) and in DN in man (220). In additionto interacting with many other matrix proteins (221,222), TSP-1also modulates their level of synthesis (223). This appearsto be primarily through its ability to activate latent TGF-(224). In vitro studies indicate that TSP-1–dependentTGF-1 activation is important in the mesangial cell responseto high glucose (225,226). Interestingly, TSP-1 null mice havea similar phenotype to TGF- null mice (227), suggesting an importantrole for the TSP-1 activation mechanism in vivo.
Decorin.
The expression of decorin (DCN), a small proteoglycan containinga single dermatan/chondroitin sulfate chain, is markedly upregulatedin MC exposed to high glucose (71,228) and in the glomerulusin DN, although protein accumulation only occurs in the latestage of the disease (24). Decorin binds to collagen type I(229) and to other extracellular proteins, including activatedTGF-, which it sequesters in the matrix (230), possibly as aternary complex with fibrillar collagen in advancing DN (24).Decorin-TGF- complexes are also excreted in the urine in lateDN (24). Administration of DCN inhibits TGF-–mediatedECM expression in experimental nephritis (230). We recentlyshowed that DCN inhibits TGF-–mediated upregulation ofPAI-1 in MC through a mechanism that involves Ca2+-dependentphosphorylation of Smad2 at a key regulatory site, thus modulatingthe TGF- Smad signaling pathway (231). Despite all these studiesthe role of decorin in DN remains unresolved.
Hyperglycemia and the Regulation of Gene Expression
Any hypothesis explaining the overall coordinated program ofchanges in gene expression in hyperglycemia that lead to glomerulosclerosismust take into account the activation mechanism of the genesinvolved. An E-box has been implicated as a carbohydrate responseelement in TGF- and several other glucose-regulated promoters(232,233). However, the concept of a single glucose responseelement being implicated in the overall changes in gene expressionbecomes less attractive when considering the very large numberof genes upregulated by hyperglycemia. Table 3 summarizes promoterregion analyses for a number of these human genes and includesknown hyperglycemia-associated stimuli, the response elements,transcription factors, and signaling pathways activating them.
Table 3. Activation of genes encoding matrix proteins in hyperglycemic conditionsa
We propose that ROS are the overall activators of these signalingpathways (Figure 1). Thus matrix-associated latent TGF- is activatedby ROS generated via extracellular formation of AGE and interactionof the active factor with its receptor activates the Smad signalingpathway. ROS generated intracellularly from glucose metabolismand AGE-RAGE interaction activates PKC (together with DAG) andMAPK pathways. This leads to the rapid activation of cellular"redox-sensitive" transcription factors such as NF-B, AP-1 (fosand jun proteins), Erg-1, and Stat1. These, together with activatedSmads (phosphorylated Smad2 and 3 complexed with Smad4), coordinatethe transcription of a wave of genes, including angiotensinogen,TSP-1, and CTGF. AngII derived from angiotensinogen stimulatesfurther generation of ROS and expression of TGF-. Secreted CTGFworks in concert with TGF- activated by TSP-1 and ROS to transactivatesubsequent waves of genes, including those encoding structuralproteins whose accumulation leads to glomerulosclerosis in DN(Figure 1).
Figure 1. Model to explain the mechanisms by which hyperglycemia promotes ECM protein accumulation by mesangial cells. Hyperglycemic conditions generate reactive oxygen species (ROS), which activate a cascade of events. Downstream of these, TGF- and connective tissue growth factor (CTGF) work in a coordinated manner to promote increased expression of ECM proteins. See text for details.
It is becoming clear that the coordinated expression of TGF-and CTGF is crucial for the induction of ECM proteins and thusfor the development of DN. The expression of some ECM proteins,such as fibronectin, is CTGF-dependent, and its promoter regiondoes not contain any Smad binding elements (SBE) (89). It isalso noteworthy that previous experiments have shown that TGF-induces fibronectin expression via a MAPK-dependent pathwayand not via a Smad-dependent pathway (250), although a recentreport indicates that a Smad-dependent pathway may operate inmice (251). In contrast, the transcription of a number of othermatrix proteins, for example collagen I, PAI-1, and TIMP-1,is TGF--dependent, and their promoter regions contain SBE (Table 3).However, it appears that increased signaling by TGF- isalso markedly influenced by CTGF, as we have found that thelatter rapidly inhibits the expression level of Smad7. Thisinhibitory Smad mediates an intracellular negative feedbackthat limits TGF- signaling (Figure 1), apparently by blockingthe association of R-Smads (Smad2 and 3) with the TGF- receptorcomplex and, thereby, their phosphorylation (252). Overexpressionof Smad7 has been shown to block TGF-–dependent inductionof collagen I in MC (253). Thus CTGF may mediate the inductionof ECM protein expression both directly and indirectly by potentiatingthe TGF-/Smad signaling pathway. A signaling receptor for CTGFhas not yet been characterized, but rapid phosphorylation ofMAPK after exposure to the growth factor indicates that onemust be present in responsive cells (179,254).
The promoters of MMP genes also show remarkable conservationof regulatory elements (255), including AP-1, ETS, and the TGF-inhibitory element, TIE. The downregulation of MMP3 (256), collagenase,MMP9, and MMP7 (257) is thought to be mediated by TIE. Thereis also evidence for modulation of MMP7 mRNA stability throughATTTA motifs in the 3'-untranslated region (258). With respectto this we have shown that high-glucose conditions switch offsynthesis of a protein, HGRG-14, in MC (259). This is achievedby production in high glucose of an HGRG-14 mRNA with a long3' UTR containing several destabilizing ATTTA motifs, whichhas a short half-life and is not translated. In low glucose,an mRNA with a short 3' UTR and no ATTTA motifs is producedthat has a longer half life and is translated (259).
The response of glomerular cells, especially MC, to hyperglycemia,is driven primarily by the generation of ROS and then TGF- andCTGF. This upregulates the transcription of many matrix genesand represses that of MMP, events which in vivo lead to glomerulosclerosis(Figure 1). It is likely that the response of other renal cellsto hyperglycemia has many features in common with this pathway,but this has been less well studied to date. There are clearlymany points at which therapeutic approaches could be tried toprovide renoprotection in diabetes. These include ACE inhibitorsand AT-1 receptor antagonists, which are already in use clinically,and novel agents to oppose the actions of ROS, TSP-1, TGF-,and CTGF. It is likely that targeting multiple points in alteredmetabolism in the diabetic kidney will be more successful inattenuating the development of DN, due to its complexity, ratherthan a single approach.
Acknowledgments
We are grateful for financial support from the Medical ResearchCouncil UK and Diabetes UK. We thank Linda Readings for secretarialsupport.
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D. Wu, F. Peng, B. Zhang, A. J. Ingram, D. J. Kelly, R. E. Gilbert, B. Gao, S. Kumar, and J. C. Krepinsky EGFR-PLC{gamma}1 signaling mediates high glucose-induced PKC{beta}1-Akt activation and collagen I upregulation in mesangial cells
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C. E Hills, P. E Squires, and R. Bland Serum and glucocorticoid regulated kinase and disturbed renal sodium transport in diabetes
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H. M.M. van Beusekom, F. Saia, J. D. Zindler, P. A. Lemos, S. L. S.-t. Hoor, M. A.H. van Leeuwen, P. J. de Feijter, P. W. Serruys, and W. J. van der Giessen Drug-eluting stents show delayed healing: paclitaxel more pronounced than sirolimus
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V. K. Pedchenko, S. V. Chetyrkin, P. Chuang, A.-J. L. Ham, M. A. Saleem, P. W. Mathieson, B. G. Hudson, and P. A. Voziyan Mechanism of Perturbation of Integrin-Mediated Cell-Matrix Interactions by Reactive Carbonyl Compounds and Its Implication for Pathogenesis of Diabetic Nephropathy
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C. Morais, J. Westhuyzen, B. Pat, G. Gobe, and H. Healy High ambient glucose is effect neutral on cell death and proliferation in human proximal tubular epithelial cells
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D. Fliser, K.-K. Wagner, A. Loos, D. Tsikas, and H. Haller Chronic Angiotensin II Receptor Blockade Reduces (Intra)Renal Vascular Resistance in Patients with Type 2 Diabetes
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F. A. van Nieuwenhoven, L. J. N. Jensen, A. Flyvbjerg, and R. Goldschmeding Imbalance of growth factor signalling in diabetic kidney disease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point?
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C. Dai, J. Yang, S. Bastacky, J. Xia, Y. Li, and Y. Liu Intravenous Administration of Hepatocyte Growth Factor Gene Ameliorates Diabetic Nephropathy in Mice
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A. Utriainen, R. Sormunen, M. Kettunen, L. S. Carvalhaes, E. Sajanti, L. Eklund, R. Kauppinen, G. T. Kitten, and T. Pihlajaniemi Structurally altered basement membranes and hydrocephalus in a type XVIII collagen deficient mouse line
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T. Hayashida and H. W. Schnaper High Ambient Glucose Enhances Sensitivity to TGF-{beta}1 via Extracellular Signal--Regulated Kinase and Protein Kinase C{delta} Activities in Human Mesangial Cells
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C. Dai and Y. Liu Hepatocyte Growth Factor Antagonizes the Profibrotic Action of TGF-{beta}1 in Mesangial Cells by Stabilizing Smad Transcriptional Corepressor TGIF
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J. Morrison, K. Knoll, M. J. Hessner, and M. Liang Effect of high glucose on gene expression in mesangial cells: upregulation of the thiol pathway is an adaptational response
Physiol Genomics,
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R. Mishra, S. N. Emancipator, C. Miller, T. Kern, and M. S. Simonson Adipose differentiation-related protein and regulators of lipid homeostasis identified by gene expression profiling in the murine db/db diabetic kidney
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C. J.M. Loomans, E. J.P. de Koning, F. J.T. Staal, M. B. Rookmaaker, C. Verseyden, H. C. de Boer, M. C. Verhaar, B. Braam, T. J. Rabelink, and A.-J. van Zonneveld Endothelial Progenitor Cell Dysfunction: A Novel Concept in the Pathogenesis of Vascular Complications of Type 1 Diabetes
Diabetes,
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Top
Abstract
Diabetic Nephropathy: The...
3, 
(TGF-
B-dependent promoter activation (111), two key events in the response to high glucose (see below). Overexpression of GFAT activates the PAI-1 promoter (112), another key event. 
