Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease: Evidence and Mechanisms of Action
Allison A. Eddy* and
Agnes B. Fogo
* Children’s Hospital and Regional Medical Center, Department of Pediatrics, University of Washington, Seattle, Washington; and Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee
Address correspondence to: Dr. Allison Eddy, Children’s Hospital and Regional Medical Center, Division of Nephrology, Mail Stop M1-5, 4800 Sand Point Way NE, Seattle, WA 98105. Phone: 206-987-2524; Fax: 206-987-2636; E-mail: allison.eddy{at}seattlechildrens.org
In 1984, Loskutoff et al. (1) purified plasminogen activatorinhibitor-1 (PAI-1) from conditioned media of cultured endothelialcells. This 50-kd glycoprotein is the primary physiologic inhibitorof the serine proteases tissue-type and urokinase-type plasminogenactivators (tPA and uPA, respectively). It now is known to mediateimportant biologic activities that extend far beyond fibrinolysisthrough interactions with its co-factor, vitronectin (also knownas protein S), and with the urokinase receptor (uPAR) and itsco-receptors (2,3). Plasma PAI-1 levels increase in responseto stress as an acute-phase protein. Usually present in traceamounts, plasma PAI-1 levels increase in several chronic inflammatorystates that are associated with chronic kidney disease (CKD),and it may contribute to the pathogenesis of the acceleratedvascular disease in this patient population (4–7). Liverand adipose tissue seem to be the primary sources of plasmaPAI-1 (8,9). Other inhibitors of plasminogen activation exist;protease nexin-1 and -2 anti-plasmin can be produced by thekidney.
Although PAI-1 normally is not produced in kidneys, synthesisby both resident and intrarenal inflammatory cells occurs inseveral acute and chronic disease states (Table 1). In the pastdecade, a growing body of experimental evidence that has derivedlargely from animal models supports the view that PAI-1 is apowerful fibrosis-promoting molecule and is a promising therapeutictarget for new drugs and biologics to combat the current CKDepidemic (Table 2). Exactly how PAI-1 promotes renal fibrosisis not understood completely. Recent studies suggest that inaddition to its ability to inhibit serine protease activitywithin vascular and extracellular compartments, PAI-1 directlymodulates cellular behavior, leading to a vicious cycle of inflammatorycell recruitment, fibroblast activation, and scar tissue accumulation.
Acute/Thrombotic Diseases
Thrombotic microangiopathy (TMA) is a pathologic lesion thatis characterized by fibrin deposition in the microvasculature,often involving glomeruli and renal arterioles. TMA characterizesrenal diseases that are caused by hemolytic uremic syndrome,preeclampsia, scleroderma, malignant hypertension, and the antiphospholipidantibody syndrome. Glomerular PAI-1 deposition is a featureof TMA (10). In children who have Escherichia coli 0157:H7 infectionand later develop hemolytic uremic syndrome (11), plasma PAI-1levels increase before the onset of renal disease. Plasma PAI-1activity correlates with renal disease severity and long-termoutcome (12–15). One pediatric study found that PAI-1activity also increases during acute renal failure of othercauses (16). Animal hemolytic uremic syndrome models that shouldprovide specific insights into the pathogenetic role of PAI-1are under development (17,18). The extent to which renal PAI-1is produced locally or derived from the plasma pool has notbeen determined.
PAI-1 expression is a feature of preeclampsia (19) and scleroderma,although experimental data suggest that PAI-1 is not essentialin the latter (20,21). Radiation nephropathy is characterizedin its early phase by TMA with PAI-1 generation, and it oftenprogresses to sclerosis. Angiotensin or aldosterone inhibitionreduces PAI-1 levels and the severity of glomerular sclerosisin experimental radiation nephropathy (22,23).
Crescentic Glomerulonephritis
Crescents develop as a result of segmental breaks of the glomerularbasement membrane (GBM), often in association with fibrinoidnecrosis. In human crescentic glomerulonephritis, PAI-1 is detectedboth in areas of glomerular necrosis and in crescents (24,25).Parietal epithelial cells are a source of PAI-1 and uPA in humancrescentic glomerulonephritis (26).
In experimental models of anti-GBM crescentic nephritis, PAI-1is produced, whereas tPA levels are suppressed, leading to decreasednet glomerular fibrinolytic activity and prolonged fibrin deposition(27). A functional role for PAI-1 in the pathogenesis of anti-GBMcrescentic glomerulonephritis was established by elegant studiesin genetically engineered mice (Table 2) (28). The PAI-1–/–mice developed fewer glomerular crescents and glomerular fibrindeposits and reduced collagen accumulation long term. In contrast,mice that were engineered to overexpress PAI-1 formed more crescentsalong with more extensive fibrin deposits and extensive collagenaccumulation. Genetic manipulations that reduce serine proteaseactivity, either plasminogen deficiency or combined uPA andtPA deficiency, also lead to aggressive injury with more extensivecrescents, necrosis, and fibrin deposition (29). Isolated tPAdeficiency causes glomerular injury that is intermediate betweenwild-type and combination PA knockout mice, whereas isolateduPA deficiency results in fewer glomerular macrophages, but,otherwise, disease severity is similar to the wild-type mice,suggesting that tPA is the primary glomerular plasminogen activator.A different outcome was observed in a passive model of anti-GBMglomerulonephritis, in which PAI-1–/– mice developedmore severe renal injury that was attributed to plasminogenactivator–dependent activation of TGF- (30). It was postulatedfurther that enhanced TGF- activity influenced CD4+ T cell responses,leading to disease exacerbation. It is possible that differencesin the mouse strain may account for some of these divergentobservations in the genetically engineered mouse studies. Itis remarkable, however, that whenever renal plasmin activityis measured in these mice, it is not found to differ significantlyfrom that of wild-type mice.
Proliferative Glomerulonephritis
PAI-1 mRNA and protein are increased in both human and animalmodels of proliferative glomerulonephritis, particularly whenlesions are severe with fibrin and crescent formation (31).In human disease, increased PAI-1 levels correlate with levelof proteinuria rather than with degree of proliferation. Ina study of 80 patients, the highest glomerular PAI-1 levelswere found in FSGS and membranous nephropathy (32).
In the rat Habu snake venom proliferative glomerulonephritismodel, PAI-1 is increased and localized to mesangial lesionsat early time points, suggesting a possible role of PAI-1 incell migration (33). In the rat mesangial proliferative modelof anti–Thy-1 antibody–mediated glomerulonephritis,PAI-1, along with growth factors such as TGF- and PDGF, areincreased, and interventions that decrease injury also lowerPAI-1 (34,35). Conversely, injecting recombinant tPA in thisrat model increases plasmin generation, with subsequent decreasein matrix accumulation (36). PAI-1 inhibition by a mutant PAI-1that binds matrix vitronectin but does not inhibit plasminogenactivator results in significant reduction in extracellularmatrix (ECM) accumulation (37). This treatment also was linkedto increased glomerular plasmin activity and enhanced ECM degradation.However, mRNA levels for genes encoding ECM proteins also weredecreased, perhaps as a consequence of decreased macrophageinfiltration and plasmin-independent effects.
PAI-1 in Chronic Progressive Renal Disease
In addition to its effects on fibrinolysis that may promotethrombotic and necrotizing renal lesions, PAI-1 has complexinteractions with matrix proteins that enhance matrix accumulationin several glomerular disease states (38–40). In humans,PAI-1 is prominent in atherosclerotic lesions and in scleroticglomeruli that are damaged as a consequence of hypertensivenephrosclerosis, diabetic nephropathy, and chronic allograftnephropathy. Plasma PAI-1 levels are increased in patients withinsulin resistance and obesity as well as overt diabetes (38–40).Within the kidney, PAI-1 protein is prominent in Kimmelstiel-Wilsonnodules, often associated with fragmented red blood cells inregions of local injury and mesangiolysis (41). Because adiposetissue is an important source of PAI-1, it also may be importantin the genesis of the nephropathy of obesity that may developeven in the absence of diabetes (42).
Although rodent models of diabetes do not develop robust glomerularsclerosis or interstitial fibrosis, there is evidence to supporta role for PAI-1 in the pathogenesis of diabetic nephropathy.In the mouse model of mild diabetic injury that is induced bystreptozotocin injection, PAI-1–/– mice have reducedalbuminuria and fibronectin levels compared with wild-type diabeticmice (43). In the db/db mouse model, PAI-1 deficiency also wasassociated with reduced albuminuria and kidney collagen levels,but a high mortality rate was observed (44). In early streptozotocin-inducednephropathy in rats, spironolactone therapy reduced PAI-1 andTGF- expression levels and matrix deposition (45). In anotherstudy, PAI-1–/– mice failed to develop the diabeticphenotype that was induced in wild-type mice by feeding a high-fatdiet (46). Furthermore, PAI-1–/– adipocytes werefunctionally distinct. They produced lower levels of severalhormones that have been identified as key mediators of the dysmetabolicsyndrome, including resistin, peroxisome proliferator–activatedreceptor-, and adiponectin (47). These studies suggest complexroles for PAI-1 in the pathogenesis of diabetes and its complications.
PAI-1 also is increased in most experimental models of glomerulosclerosis,including cyclosporin-induced glomerulosclerosis, radiationnephropathy, various models of FSGS, chronic anti–Thy-1nephritis, diabetic nephropathy, aging, and chronic allograftnephropathy (38,48). Two powerful fibrogenic systems are potentPAI-1 inducers: TGF- and the renin-angiotensinaldosterone system.Because angiotensin, PAI-1, and TGF- often are coexpressed inchronic renal disease, it has been challenging to decipher theindependent contributions of each molecule to the scleroticprocess (49). However, in the anti–Thy-1 model, combinedTGF- and angiotensin inhibition reduces PAI-1 expression andglomerular matrix accumulation and is more effective than eithertherapy alone (35).
Studies in the 6 knockout mice provide additional insights.The v6 integrin is involved in TGF- activation. 6–/–mice are protected from fibrosis after unilateral ureteral obstruction(UUO) and do not show increased active TGF- and PAI-1 like thewild-type mice (50,51). However, PAI-1 expression and fibrosis,but not TGF-, are restored to wild-type levels by infusing angiotensin,supporting a direct link among angiotensin, PAI-1, and fibrosis.Molecular studies indicate that angiotensin-dependent, TGF-–independentinduction of PAI-1 gene expression involves the AT1 receptorand a glucocorticoid response element in the PAI-1 promoter(40,52). AT1 receptor blockade but not nonspecific antihypertensivetreatment reduces renal PAI-1 expression that is induced byangiotensin II (AngII) infusion (53). Aldosterone also enhancesangiotensin-induced PAI-1 expression. In a small study of hypertensivehuman kidney transplant recipients, elevated plasma PAI-1 levelswere decreased by treatment with angiotensin receptor blockersbut not by nifedipine (54).
Additional CKD models are remarkably attenuated when PAI-1 isabsent (Table 2). Sclerosis-prone 129Sv mice that are bred togenerate a PAI-1 null genotype are completely protected fromglomerular scarring and tubulointerstitial fibrosis after 5/6nephrectomy (Figure 1) (55). In vitro, PAI-1–/–podocytes synthesize less collagen in response to AngII thanwild-type cells (56). PAI-1 deficiency also reduces vascularsclerotic lesions that develop in wild-type mice that are exposedto AngII and salt loading or nitric oxide inhibition by L-NAME(57–59). PAI-1 deficiency protects against interstitialfibrosis that is induced by protein overload (60). In the UUOmodel, PAI-1–/– mice have reduced renal collagen,whereas PAI-1 overexpressing mice develop worse fibrosis (Figure 2)(61,62). PAI-1 levels are increased in TGF-–overexpressingmice that develop progressive glomerulosclerosis (63). Whenthese TGF- transgenic mice are bred with PAI-1–/–mice, both glomerular and interstitial matrix deposition arereduced (63). Several of these in vivo studies uncovered anunexpected finding, namely that the fibrosis-reducing effectsthat are associated with PAI-1 deficiency often occurred withoutmeasurable differences in renal protease activity, whereas thenumber of inflammatory macrophages and myofibroblasts were reduced,especially during the early response to injury.
Figure 1. Plasminogen activator inhibitor-1 (PAI-1) deficiency attenuates glomerulosclerosis in mice with remnant kidneys. Ten weeks after sclerosis-prone 129Sv mice underwent 5/6 nephrectomy, glomerulosclerosis and interstitial fibrosis were evident (A). These lesions failed to develop in 129Sv /PAI-1–/– mice (B). Magnification, x200 (periodic acid-Schiff).
Figure 2. PAI-1 deficiency attenuates interstitial fibrosis in mice with obstructive nephropathy. After complete ureteral obstruction, interstitial fibrosis rapidly develops. Compared with C57BL/6 PAI-1 wild-type (WT) mice, the obstructed kidneys of PAI-1–/– mice demonstrate less fibrosis (total collagen and Sirius red–stained interstitial area). Disease attenuation in the PAI-1–/– mice was associated with fewer F4/80+ interstitial macrophages and -smooth muscle actin (-SMA)-positive interstitial myofibroblasts but not with detectable differences in renal plasmin activity. Graphs show the quantitative data; representative photomicrographs are shown to the right for Sirius red collagen, F4/80, and -SMA staining, respectively. *P < 0.05. Magnification, x400. Reprinted from reference (61), with permission.
It was suggested recently that early renal "scars" remodel andmay even disappear. Regression has been clearly demonstratedin certain glomerular diseases that are associated with expansionof the mesangial matrix (human diabetes, the acute Thy-1 ratglomerulonephritis model) and in models of sclerosis (5/6 nephrectomy,aging) (64,65). In the 5/6 nephrectomy glomerulosclerosis modelinhibitors of angiotensin or aldosterone given alone or in combinationsignificantly decrease and sometimes reverse existing glomerulosclerosis.This beneficial effect is strongly linked to decreased glomerularPAI-1 expression (Figure 3) (66,67). Similar results are seenin aging rats, where existing aortic and glomerular sclerosisare reversed by high dose AT1 receptor blockade and are associatedwith decreased PAI-1 levels (68). In the 5/6 nephrectomy model,glomerulosclerosis regression is associated with increased plasminactivity (67).
Figure 3. PAI-1 immunostaining in 5/6 nephrectomized rats. At 8 wk after 5/6 nephrectomy, sclerosis was moderately advanced with corresponding increased PAI-1 immunostain in sclerotic glomeruli and in the tubulointerstitium (brown stain; A). Regression of sclerosis was induced by week 12 in some rats that were treated with high-dosage angiotensin receptor blocker starting at 8 wk, with corresponding marked decrease in PAI-1 immunostain (B). Magnification, x200 (PAI-1 immunostain). Reprinted from reference (67), with permission.
The molecular composition of sclerotic glomeruli differs fromthat of the normal mesangial matrix and seems to be more resilientto proteolytic degradation, perhaps explaining why glomerulosclerosisregression is not achieved in all 5/6 nephrectomized rats thatare treated with high-dose renin-angiotensin system blockers.The same distinction also applies to the interstitium, whereinterstitial matrix may expand transiently during acute self-limiteddiseases such as acute tubular necrosis and nephrotic syndrome,whereas interstitial fibrosis that is induced by chronic andprogressive injury is more resistant to remodeling and regression(69). Nonetheless, a recent mouse UUO study reported convincingevidence of interstitial matrix remodeling when UUO was releasedafter 7 d (70). The specific molecular mechanisms that reverseinterstitial and glomerular deposits of fibrotic matrix proteinsremain to be determined, but it is tempting to speculate thatPAI-1 might be one molecular switch: On during fibrosis andoff again during regression.
PAI-1 is synthesized as a single-chain glycopeptide that issecreted rapidly; platelets seem to be the only cell that iscapable of its intracellular storage. In CKD, PAI-1 accumulatesin the interstitium (71,72). PAI-1 spontaneously converts toa more stable inactive molecule unless it interacts with oneof its binding partners: The matrix molecule vitronectin, tPAor uPA, or possibly LDL receptor–associated protein (LRP),a multiligand scavenging and signaling receptor also known asthe -2 macroglobulin receptor (73). PAI-1 converts to its inactiveform when a flexible joint in the reactive center loop regionbends, thereby making tPA and uPA binding sites inaccessible(74). Vitronectin accumulation at sites of renal injury maytrap active PAI-1 as a result of high-affinity binding. Thefunction of PAI-1 in tissue pathology is likely to depend onwhether vitronectin is present. PAI-1 expression is highly regulatedand may be induced in a variety of cells. Numerous growth factors,coagulation factors, metabolic factors, hormones, and environmentalfactors that are implicated in kidney disease pathogenesis havebeen shown to induce PAI-1 expression (reviewed in reference[38]). More recently identified PAI-1 agonists include C-reactiveprotein (75), thymosin 4 (76), CD40L (77), and sterol regulatoryelement–-binding proteins (78). Prostaglandin E1 and vitaminD have been reported to decrease PAI-1 expression (79,80).
Plasmin
Although plasminogen is not produced in the kidney, plasma plasminogenreadily can escape to extravascular sites (81). Active plasminis generated by tPA- or uPA-dependent cleavage of the latentzymogen plasminogen (Figure 4). The active disulfide-linkedhomodimer is required to degrade fibrin and remodel thromboticclots. Plasmin activity is particularly important within vascularspaces. Fibrin also may be required for crescent formation (82).What remains unclear is the extent to which fibrin(ogen) accumulateswithin renal mesangial and interstitial matrices and whetherits presence in such sites facilitates scar formation. In contrast,fibrin as an early "provisional matrix" has been consideredan important precursor to pulmonary fibrosis. However, the severityof pulmonary fibrosis is not attenuated in fibrinogen-deficientmice, indicating that fibrin does not seem to be essential forfibrogenesis in the lung (83,84). Similar studies have not yetbeen performed to determine whether fibrinogen plays a rolein progressive kidney disease.
Figure 4. Schematic summary of protease inhibition–dependent extracellular PAI-1 effects that may influence fibrosis severity. The latent zymogen plasminogen is a major substrate for urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), although each serine protease has additional cleavage targets that have been implicated in renal fibrosis. The protease plasmin also cleaves several proteins that are expressed during fibrogenesis. Plasminogen cleavage also may lead to the liberation of kringle domains as angiostatin, an angiogenesis inhibitor. MMP, matrix metalloproteinase; HGF, hepatocyte growth factor. Illustration by Josh Gramling—Gramling Medical Illustration.
Although fibrin is the preferred plasmin substrate, plasminalso cleaves other proteins that are thought to be involvedin fibrosis. First, plasmin activates several latent metalloproteinases(MMP) (85). The MMP are a large family of matrix-degrading enzymes.The collagenase IV enzymes or gelatinases are abundant in thekidney, MMP-9 in particular. In response to chronic injury thatis induced by UUO, MMP-9 activity declines, a change that waspredicted to impair matrix turnover and promote fibrosis (86).However, other studies demonstrate that MMP-9 also degradestubular basement membranes, an effect that may promote fibrosisby facilitating the migration of matrix-producing transdifferentiatedtubular epithelia into the interstitium (87). Furthermore, throughinteractions with v3 integrins, the gelatinases may influencecellular behavior directly (88). When transgenic mice were generatedto overexpress MMP-2 in renal proximal tubules, the mice developedinterstitial fibrosis and tubular atrophy (89). Therefore, atthis time, it is unclear whether renal MMP activation by plasmin(or other proteases) attenuates or promotes renal fibrosis.Plasmin also can activate prourokinase (90).
Second, plasmin has limited ability to degrade certain matrixproteins directly, including fibronectin, laminin, entactin,tenascin-C, thrombospondin, and perlecan (38). By degradingECM, plasmin also may release sequestered growth factors thatmodulate fibrosis severity. Studies by Noble et al. supportthe view that intraglomerular plasmin activity promotes matrixdegradation (91). Third, in vitro, plasmin is a potent activatorof latent TGF- (92). However, the primary pathway(s) by whichTGF- is activated during progressive renal damage remains unknown.Plasmin remains a candidate. Fourth, in addition to thrombin,the protease-activated receptor-1 can be activated by plasmin.When plasmin activates tubular cell protease-activated receptor-1,it may initiate their transdifferentiation and promote fibrosis(93). This interaction also inhibits monocyte apoptosis (94).
With so many possible activities, it was unclear whether increasesin renal plasmin activity promote or attenuate CKD. This questionwas complicated further by results of studies of CKD modelsin PAI-1 genetically manipulated mice. Although PAI-1 levelscorrelate with disease severity, there is no detectable differencein renal plasmin activity (61,62). For clarification of therole of plasmin, UUO was induced in plasminogen wild-type andknockout mice. Renal fibrosis was less severe in the plasminogen-deficientmice, associated with lower levels of active TGF- (93,95). Thesefindings do contrast with outcomes in the bleomycin-inducedlung injury model, in which fibrosis is worse in plasminogen-deficientmice, suggesting that the fibrogenic effects of plasminogenmight be organ specific (96).
One additional effect of plasminogen deserves mention. The angiogenesisinhibitor angiostatin is a plasminogen cleavage product thatcomprises three to five of its kringle domains. Angiostatinbinds to several endothelial cell surface receptors, but italso may interact with other cells. Diabetic rats that weretreated with an adenoviral vector–expressing angiostatindeveloped less albuminuria and glomerular hypertrophy associatedwith downregulation of TGF- and vascular endothelial growthfactor levels (97).
On the basis of currently available data, it seems that renalPAI-1 expression does not necessarily alter renal plasmin activity.Other regulators, such as -2 anti-plasmin, might be more critical(60,98). Plasmin has several proteolytic targets and can triggerreceptor-dependent effects, and, together, its activities favorfibrosis development, at least in the UUO model. It is possiblethat many of the profibrotic effects of PAI-1 align more closelywith its ability to block plasmin-independent proteolytic actionsof tPA and uPA.
tPA
tPA is produced primarily by endothelial cells, but it alsois synthesized by many other cells, including monocytes andfibroblasts. It traditionally has been viewed as an intravascularprotease because of its need for fibrin to optimize its plasminogenactivator activity. Other important actions of tPA were identifiedrecently. Basal renal tPA activity is low (detected in glomerularcells and collecting duct epithelia). Decreased glomerular tPAactivity has been implicated in the pathogenesis of crescenticglomerulonephritis; genetic tPA deficiency worsened disease,whereas recombinant tPA has been reported to reduce glomerularmatrix expansion (29,36). Renal tPA activity increases afterUUO (61,71). During chronic tubulointerstitial disease, thepredominant effect of tPA seems to enhance renal fibrosis (87).One relevant mechanism is MMP-9 activation in the proximityof tubular basement membranes. Although total renal MMP-9 activitydeclines after UUO, preservation of its activity by tPA at specificsites of chronic damage may be harmful (86). In addition toprotease activity, tPA promotes monocyte adhesion and activatesfibroblast intracellular signaling pathways by binding to LRP(99,100). tPA mediates vascular smooth muscle cell contractionvia interactions that involve LRP and v3 integrin (101). Italso may bind to other cellular receptors such as annexin 2,a plasmin(ogen) co-receptor, and the mannose receptor (102).
uPA
Synthesized by tubular epithelial cells and secreted apicallyinto the urinary space, the kidney is a rich source of uPA.At sites of damage, uPA also may be produced by inflammatorycells and activated fibroblasts. The primary physiologic roleof renal uPA is unknown; it might play a role in nephrolithiasisprevention (103). In response to chronic damage that is inducedby UUO, renal uPA mRNA levels and protease activity increasedespite significant increases in PAI-1 (61,71). uPA activityhas been associated with several proteolytic effects that shoulddecrease fibrosis. Although plasminogen is the preferred uPAsubstrate, uPA also degrades some matrix proteins, such as fibronectin(104), and it activates latent hepatocyte growth factor (HGF)(105) and membrane-type metalloproteinases (106). HGF has beenshown to attenuate fibrosis in several experimental models (107).In experimental pulmonary fibrosis, intratracheal uPA therapyincreased active HGF levels and reduced scarring (108). However,we recently found that the severity of inflammation, interstitialmyofibroblast infiltration, and renal fibrosis were identicalin uPA wild-type and knockout mice after UUO (109).
Although studies in genetically engineered mice have provedto be useful tools for delineating the mechanism of action ofPAI-1 in CKD, it needs to be acknowledged that men and micemay not be the same and that only a limited number of kidneydisease models have been investigated thus far. Evidence isemerging slowly in favor of the concept that the roles of theserine proteases and their inhibitors are cell specific anddistinctly different in the glomerular and tubulointerstitialregions where levels of tPA, uPA, uPAR, and LRP in particularmay differ. For example, in contrast to the results of the studiesin the chronic UUO model, in vitro (110) and in vivo studies(36) have shown that glomerular plasmin activity that is generatedby plasminogen activators is associated with reduced matrixaccumulation. It also remains plausible that undisclosed consequencesof gene ablation, such as compensatory upregulation of othergenetic programs (e.g., protease nexin-1) may account for someof the findings. Nonetheless, current evidence suggests thatbiologic effects beyond protease inhibition likely contributeto the striking ability of PAI-1 to promote fibrosis. PAI-1also influences the recruitment and/or behavior of several celltypes that are involved in the fibrogenic response. In particular,although a unique PAI-1 receptor has not been identified, PAI-1modifies the function of the uPAR and several of its co-receptors.
Figure 5. Schematic summary of cellular receptor–dependent effects of PAI-1 that may modulate fibrosis severity. The extracellular matrix protein vitronectin (VN) anchors cells by binding that occurs between its somatomedin B domain and the urokinase receptor (uPAR). Immediately adjacent to this vitronectin domain is an arginine-glycine-aspartate (RGD) sequence that binds the v3 integrin receptor. In the presence of PAI-1, several outcomes are possible. (A) Cells may detach from their vitronectin anchors. PAI-1 has higher affinity than uPAR for the somatomedin B domain of vitronectin; this interaction also may disrupt RGD-integrin binding. uPAR-bearing cells thus are detached from their vitronectin matrix connections and liberated to participate in interactions that may involve uPAR and any of its co-receptors: Integrins, mannose-6 phosphate/insulin growth factor II receptor (Man6P-R), gp130, Endo 180, or the LDL receptor–associated protein (LRP). (B) Alternatively, PAI-1 might bind to cells via uPAR-bound uPA. Then this entire complex usually is degraded by LRP-dependent endocytosis, a process that leads to PAI-1 degradation. (C) PAI-1 can interact directly with LRP and thereby direct the movement of cells such as monocytes toward PAI-1. Illustration by Josh Gramling—Gramling Medical Illustration.
Vitronectin/v3 Interactions
PAI-1 regulates cellular adhesion and migration via high-affinityinteractions with its co-factor vitronectin. The function ofPAI-1 in tissue remodeling and fibrosis likely differs in thepresence and absence of vitronectin. uPAR and PAI-1 competefor a common binding site in the somatomedin B domain of vitronectin(2,3,111). This domain is adjacent to an RGD sequence that bindsv3 integrin. PAI-1 has "de-adhesive" actions, as it blocks uPAR–vitronectininteractions and subsequently impairs a cell’s abilityto bind to v3 integrins (112,114). Depending on the cellularand matrix milieu within which PAI-1 deposits, PAI-1 may eitherfacilitate or impair cell migration. For example, for severalcarcinomas, PAI-1 expression predicts a highly invasive andmetastatic phenotype (114). When PAI-1 is expressed in earlyfibrotic lesions that are rich in fibronectin, its ability todetach v3-bearing cells (e.g., fibroblasts) from vitronectinanchors liberates cells, allowing them to migrate along fibronectinmatrices and advance scar formation. From the UUO studies thatwere performed in PAI-1 engineered mice, PAI-1 levels predictedinterstitial myofibroblast density and fibrosis severity: Greaterin PAI-1–overexpressing mice and less in PAI-1–deficientmice compared with wild-type mice (61,62). Vitronectin (alsoknown as S protein) also inhibits formation of complement C5b-9membrane attack complex. Because the terminal complement cascadehas been implicated in the progression of proteinuric renaldisease, it is plausible PAI-1 might influence this function,although such a role has yet to be demonstrated (115).
Urokinase Receptor/LDL Receptor–Associated Protein Interactions
The urokinase receptor (uPAR or CD87), a highly glycosylated50- to 65-kD protein, binds to both latent and active uPA, providinga unique mechanism to concentrate proteolytic activity in pericellularregions, where it potentially facilitates cell migration (112).The uPAR is expressed by many cells, including monocytes, neutrophils,activated T cells, endothelial cells, glomerular epithelialand mesangial cells, renal tubular epithelial cells, fibroblasts,and myofibroblasts (10,116–120). When PAI-1 binds to receptor-bounduPA, it triggers internalization and degradation of both uPAand PAI-1 (along with uPAR and possibly uPAR co-receptors, e.g.,integrins) via endocytic LRP receptors. This seems to be theprimary cellular pathway for PAI-1 degradation. In uPAR–/–mice, renal fibrosis is more severe, possibly due in part toenhanced PAI-1 interstitial accumulation (71). This endocyticmechanism also may account for some of the cell-detachment effectsthat are orchestrated by the presence of PAI-1 (121).
Although uPAR itself is a nonsignaling receptor that is anchoredto the plasma membrane by glycosylphosphatidylinositol, itsectodomain interacts with several co-receptors that confer diversebiologic properties, including fibrotic reactions. Exactly howthe presence of PAI-1 might alter uPAR co-receptor activitiesrequires further investigation. Furthermore, recent data suggestthat uPA itself may bind directly to some of the co-receptors.Known uPAR co-receptors include several integrins, L-selectin,LRP, the IL-6 gp130 receptor, uPAR-associated protein (or Endo180),and the mannose-6-phosphate/insulin growth factor II receptor(CD222).
uPAR does not seem to be expressed in normal kidneys, but itis present in several renal disease states, including endotoxemia,acute tubular necrosis, thrombotic microangiopathy, crescenticglomerulonephritis, pyelonephritis, acute and chronic allograftrejection, diabetic nephropathy, and obstructive nephropathy(10,71,118,122–126). Compared with wild-type mice, uPAR–/–mice develop more severe fibrosis after UUO (71); uPAR deficiencydoes not alter the severity of crescentic glomerulonephritis(29). In addition to uPA, uPAR has two ligands: Vitronectinand high molecular weight kininogen (Hka) (127). Hka and bradykininare generated by kallikrein-mediated kininogen cleavage. Bradykinin,signaling via its B2 receptor, elicits important antifibroticeffects that may contribute to the renoprotective effects ofangiotensin-converting enzyme inhibitors (128,129). Whetherspecific interactions between Hka and uPAR influence fibrosisseverity is not yet clear.
An important feature of CKD is the progressive rarefaction ofthe interstitial capillary network, which aggravates hypoxiaand oxidant stress, thereby contributing to the spiral of worseningrenal damage. Angiogenesis failure characterizes the renal interstitialenvironment in CKD (130). Recent animal studies have reportedthat administration of proangiogenic factors such as vascularendothelial growth factor or angiopoietin-1 reduce renal fibrosis(131,132). PAI-1 modulates angiogenesis, although its primaryin vivo effect remains controversial: Inhibition has been observedin many experimental conditions (133–135). In CKD, PAI-1accumulates primarily within the interstitial matrix that surroundsinterstitial capillaries. Although the specific mechanisms involvedremain to be clarified, cellular receptors may play a role asangiogenesis is enhanced in the presence of uPAR (71,136).
Monocyte/Macrophage Chemotactic Receptors
Studies in genetically engineered mice uncovered an apparentrelationship between macrophage recruitment and PAI-1 levels.An in vitro chemotaxis experiment suggested that PAI-1 itselfmight have monocyte chemoattractant properties (61). This effectseems to be dependent on LRP expression (137). Macrophage recruitmentthat leads to TGF- production seems to be an important mechanismwhereby PAI-1 enhances renal fibrosis (37,61,62). In addition,uPAR can be cleaved by proteases to generate a soluble formthat comprises domains 2 and 3. Soluble uPAR triggers monocytechemotaxis by binding the FPRL1/LXA4 (formyl-methionyl-leucyl-proline–likereceptor-1/lipoxin A4 receptor) (138). How the presence of PAI-1influences uPAR shedding by proteases remains to be determined.
One of several factors that influence plasma levels in humansis PAI-1 genotype. Higher levels correlate with polymorphicvariance in the number of guanine bases (4G versus 5G) in thepromoter at position –675. The 5G variant binds the E2Ftranscription repressor, whereas 4G fails to do so and is associatedwith higher plasma levels. Therefore, PAI-1 genotype might bea predictor of CKD progression. The PAI-1 4G/4G genotype waslinked to increased risk for vascular complications in patientswith diabetes, especially when superimposed on the angiotensin-convertingenzyme D/D genotype that is associated with increased renin-angiotensinsystem activity (139). Increased PAI-1 plasma levels and 4G/4GPAI-1 genotype also have been linked to increased risk for chronicallograft dysfunction (140). In patients with lupus nephritis,the 4G/4G PAI-1 genotype has been associated with higher diseaseactivity and more severe necrotizing lesions than those withthe 5G genotype, suggesting that PAI-1 influences glomerularproliferative lesions as well as sclerosis (141,142). Althoughmore studies are needed, thus far, PAI-1 genotype seems to bea better predictor of atherosclerosis (including renovascularlesions) and cardiovascular disease than CKD risk (143,144).With rare exception (141), PAI-1 genotype has not been predictiveof diabetic nephropathy, perhaps not surprising because so manyother PAI-1 agonists are elevated in patients with diabetes(38).
PAI-1 is a multifunctional glycoprotein with impressive fibrosis-promotingeffects in the kidney. High renal PAI-1 levels seem to predicta bad long-term outcome, although more rigorous clinical studiesstill are needed to establish its prognostic predictive valuein humans. In lesions that are characterized by the presenceof fibrin, such as those that occur in certain glomerular andvascular diseases, inhibition of fibrinolysis closely associateswith chronic damage. Switching off PAI-1 has been shown experimentallyto prevent CKD progression and may even facilitate its regression.By contrast, in the renal interstitium, where PAI-1 may accumulateas a result of the presence of vitronectin, its primary fibrogeniceffects align more closely with its ability to facilitate cellmigration (monocytes and myofibroblasts in particular), althoughother potential mechanisms remain to be elucidated (Figure 6).Among the many renoprotective properties of the AngII inhibitorsis their ability to suppress PAI-1. Development of selectiveanti–PAI-1 therapeutic agents is under way, but the idealantifibrotic agent has not yet been discovered (145). Much stillremains to be disclosed about the role of PAI-1 in CKD. Forexample, will PAI-1 genotype or kidney expression levels proveto be useful predictors of CKD risk in humans? If AngII andTGF- activities are therapeutically blocked, then can PAI-1still be synthesized and promote fibrosis? Is PAI-1’srole as an inhibitor of fibrinolysis relevant to CKD pathogenesis?And much remains to be learned about the receptor-dependentbiologic effects of PAI-1 that are relevant to renal fibrogenesisand regression.
Figure 6. Schematic summary of the primary effects of PAI-1 in chronic kidney disease (CKD). Renal PAI-1 expression can be induced by a number of factors involved in disease pathogenesis. TGF- and angiotensin II are widely recognized inducers of PAI-1, but many other factors stimulate PAI-1 expression in CKD. The ability of PAI-1 to reduce plasmin activity seems to promote thrombotic and necrotizing glomerular lesions, many of which progress to sclerosis. In other glomerular lesions, PAI-1 inhibits extracellular matrix breakdown. Within the tubulointerstitium, the profibrotic effects of PAI-1 align more closely with its ability to promote migration of monocytes/macrophages, transdifferentiated tubular epithelia and (myo)fibroblasts in particular. Illustration by Josh Gramling—Gramling Medical Illustration.
Acknowledgments
We acknowledge research grant support from the National Institutesof Health: DK54500 (A.A.E.), DK56942 (A.B.F.), and DK44757 (A.B.F.,A.A.E.).
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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-2 anti-plasmin can be produced by the kidney. 
(30). It was postulated further that enhanced TGF-
, and adiponectin (47). These studies suggest complex roles for PAI-1 in the pathogenesis of diabetes and its complications. 
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Fibrosis-Promoting Consequences...
Protease-Dependent Effects of...
