REVIEW J Am Soc Nephrol 11: 574–581, 2000

Matrix Metalloproteinases in Renal Development and Disease

OLIVER LENZ,* SHARON J. ELLIOT,* and WILLIAM G. STETLER-STEVENSON† *Renal Cell Biology Laboratory, University of Miami School of Medicine, Miami, Florida; and †Extracellular Matrix Pathology Section, DCS, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Remodeling of extracellular matrix (ECM) is an important known MMP, MMP-1, MMP-13, MMP-3, MMP-2, MMP-9, physiologic feature of normal growth and development. Many and MT-1-MMP have been extensively studied in the kidney. diseases have been associated with an imbalance of ECM Four members in this group of collagenases, MMP-1, MMP-2, synthesis and degradation, which may result in an accumula- MMP-8 and MMP-13, share the ability to degrade fibrillar tion of ECM molecules (1). In the kidney, these processes can collagens (29–31). The resulting fragments denature sponta- lead to interstitial fibrosis, which has been reviewed elsewhere neously under physiologic temperatures, which then can be (2–4), and glomerulosclerosis (5). Progressive glomeruloscle- further degraded by other proteases. rosis leading to end-stage renal failure is a complication of a There are two gelatinases, MMP-2 and MMP-9. While shar- variety of diseases, such as diabetes mellitus, glomerulonephri- ing the ability to degrade both basement membrane collagens tis, focal sclerosis, chronic transplant rejection, or obstruction and gelatins, their substrate specificity is not identical. MMP-2 (6–11). Although many studies have tried to elucidate the degrades fibronectin and laminin, and has significantly less pathogenesis, the exact underlying mechanisms are still not activity against types IV and V collagen than MMP-9 (32–34). completely understood. While increased synthesis of ECM They also vary greatly in their promoter structure, and thus in certainly plays an important role, recent studies have focused their expression pattern (35). MMP-2 and MMP-9 are also on the role of degradative systems. The major physiologic unique in that they form proenzyme complexes with their regulators of ECM degradation in the glomerulus are matrix endogenous inhibitors tissue inhibitor of metalloproteinase-2 metalloproteinases (MMP) (12). Both glomerular disease and (TIMP-2) and TIMP-1, respectively (36–39), which have been normal renal development are characterized by a high rate of shown to be expressed in human glomeruli (40). Although the ECM turnover. Since the underlying mechanisms may follow roles of these complex formations in ECM turnover have not similar patterns, we will discuss the role of MMP in chronic been completely elucidated, they may at least in part account glomerular disease and normal renal development, and we will for the selective inhibition of MMP-2 by TIMP-2. Other pos- highlight implications of experimental findings for human re- sible roles of complex formation include regulation of cell nal disease. surface localization of MMP via integrin receptors such as ␣ VB3 (41) (vide infra), mediation of the cell surface activation Structure and Function of MMP of MMP by MT-1-MMP (26,42,43), as well as regulation of MMP are a large family of zinc-dependent matrix-degrading MMP (44) and/or TIMP (45,46) cell growth-modulating activ- enzymes, which include the interstitial collagenases, stromel- ity. However, the growth-regulating activity of MMP and ysins, gelatinases, elastases, and secreted, as well as mem- TIMP in renal development and disease has not been directly brane-type, RXKR containing MMP (13–18) (Table 1). They demonstrated. have been implicated in invasive cell behavior (18,19), embry- Stromelysin-1 and stromelysin-2 share almost identical sub- onic development (20–22), interstitial fibrosis (23), and glo- strate specificity, but, like the gelatinases, are differentially merulosclerosis (24,25). MMP share several structural and regulated. With the exception of human T lymphocytes, functional properties, which include pre/pro-peptide (26), stromelysin-2 is constitutively expressed at low levels or is hinge, hemopexin-like (except MMP-7), and catalytic zinc- absent, while stromelysin-1 can be induced by the cytokines binding domains (27,28) (Figure 1). They synergistically de- interleukin-1␤ and tumor necrosis factor-␣, the growth factors grade a broad range of ECM compounds. Of the currently epidermal growth factor and platelet-derived growth factor, and phorbol esters, and inhibited by transforming growth fac- tor-␤ (TGF-␤) and retinoic acid (35). Received July 12, 1999. Accepted October 9, 1999. Members of the RXKR group share the recognition motif that Correspondence to Dr. William G. Stetler-Stevenson, Extracellular Matrix consists of the highly basic sequence of amino acid residues Pathology Section, LP/DCBDC/NIC/NIH, Building 10, Room 2A33, 9000 arginine,arginine/glutamine,lysine,arginine. This sequence of res- Rockville, Pike, Bethesda, MD 20892. Phone: 301-496-2687; Fax: 301-402- 2628; E-mail: [email protected] idues is recognized by the Golgi-associated proteinase furin, 1046-6673/1103-0574 which has been implicated in the activation process of these MMP Journal of the American Society of Nephrology (14,43). The membrane-type MMP contain a transmembrane Copyright © 2000 by the American Society of Nephrology COOH-terminal end, and they have been shown to play a role J Am Soc Nephrol 11: 574–581, 2000 MMP in Renal Development and Disease 575

Table 1. The matrix metalloproteinase (MMP) family: current nomenclature and substrate specificity

Mass (latent) Group MMP Enzyme (kD) Substrate(s)

Interstitial collagenase MMP-1 Collagenase-1 55 Collagens I, II, III, VII, VIII, X; aggrecan MMP-8 Collagenase-2 75 Collagens I, II, III PMN-collagenase MMP-13 Collagenase-3 65 Collagens I, II, III Stromelysin MMP-3 Stromelysin-1 57 Aggrecan; collagens III, IV, V, IX, XI; gelatins; fibronectin; laminin; elastin MMP-7 Matrilysin 28 Aggrecan; collagen IV; fibronectin; laminin; gelatins PUMP MMP-10 Stromelysin-2 57 Aggrecan; collagens III, IV, V, IX; gelatins; fibronectin; laminin; elastin Gelatinase MMP-2 Gelatinase A 72 Collagens IV, V, VII, X, XI; aggrecan; gelatins; fibronectin; laminin; elastin MMP-9 Gelatinase B 92 Collagens IV, V; aggrecan; gelatins; elastin ␣ Secreted RXKR MMP-11 Stromelysin-3 51 1-Antitrypsin Membrane-type MMP14 MT-MMP-1 63 Pro-MMP-2; collagen I; fibronectin RXKR MMP-15 MT-MMP-2 72 MMP-16 MT-MMP-4 64 Pro-MMP-2 MMP-17 MT-MMP-5 ? Elastase MMP-12 Metalloelastase 54 Elastin

in the regulation of proenzyme processing of the pro-MMP-2/ play a crucial role in maintaining the balance between ECM TIMP-2 complex (42,43). synthesis and degradation.

MMP in Glomerular Disease MMP in Noninflammatory Glomerular Disease Mechanisms of Action The role of MMP and their endogenous inhibitors in the The major physiologic regulators of ECM degradation in the development of glomerular damage has been studied in a glomerulus are MMP (12). A balance between ECM synthesis variety of experimental conditions (Figure 2). In general terms, and degradation is a prerequisite for maintaining the structural a downregulation of MMP has been associated with progression and functional integrity of the glomerulus. Thus, changes in in noninflammatory diseases such as hypertensive glomeruloscle- MMP expression or activity will directly translate into altered rosis (51,52), growth hormone excess (25,53), hydronephrosis ECM turnover, which may lead to glomerular scarring and a (54–56), hypercholesterolemia (57), heroin nephropathy (58), cy- decline in renal function. closporine nephrotoxicity (59), or sex-related changes in the aging Many forms of glomerular disease are characterized by a kidney (60). In this review, we chose diabetic nephropathy as one change in cellularity, which in turn may affect ECM compo- example to illustrate the link between progressive glomeruloscle- sition and turnover. MMP have been shown to influence the rosis and MMP expression. behavior of glomerular cells either directly or via the genera- Diabetic nephropathy has been studied extensively, as it is tion of ECM cleavage products (44,47). the leading cause of end-stage renal disease in the United MMP may also indirectly influence ECM turnover via the States, Japan, and Europe (61–64). Histologically, glomerular regulation of certain growth factors. Recently, regulation of hypertrophy, glomerular basement membrane thickening, and growth factor activity by MMP has been observed in MMP- mesangial expansion characterize diabetic nephropathy 9-deficient mice, which exhibit abnormal growth plate vascu- (65,66). In vitro, studies of the effect of high ambient glucose larization and ossification (48), and binding proteins for insu- on ECM turnover revealed an increased expression of matrix lin-like growth factor-1 have been identified as substrates of molecules, while the activity of MMP, namely MMP-2 and MMP (49). MMP-9, were decreased in mesangial cells (67–69). These Finally, in diseases with altered matrix composition, such as findings were confirmed in streptozotocin (STZ)-treated dia- Alport disease, an increased susceptibility of the basement betic rats, in which not only a downregulation of MMP (70– membrane to degradation by MMP has been postulated to 72), but also an upregulation of TIMP-1 was observed (24,73). cause glomerular damage (50). These findings illustrate that The latter could accentuate the imbalance between matrix MMP are involved at several levels of ECM turnover, and thus synthesis and degradation. Kidney biopsies from patients with 576 Journal of the American Society of Nephrology J Am Soc Nephrol 11: 574–581, 2000

Figure 1. Domain structure of the matrix metalloproteinases (MMP). (A) Simplified schematic of the minimal domain structure of the MMP. Most MMP have the same basic domain structure consisting of signal (pre-), pro-, and catalytic domains. The prodomain contains a highly conserved sequence (shown in single letter amino acid code) that is responsible for maintaining the latency of the proenzyme. (B) Additional domains observed in various members of the MMP family. The F denotes location of the furin RXKR cleavage site of MMP-11 Figure 2. Schematic overview of glomerulosclerosis disease progres- and the membrane-type MMP. The FBN represents the type II repeats sion. This diagram compares and contrasts the disease process asso- of fibronectin found in the gelatinases. C represents a type V collagen- ciated with both inflammatory mechanisms and noninflammatory like sequence found in MMP-9. H denotes the flexible hinge region mechanisms that can result in glomerulosclerosis. that usually separates the catalytic and hemopexin-like (PEX) do- mains. TM represents the transmembrane domain characteristic of the membrane-type (MT)-MMP. at least slow progression of diabetic nephropathy in a number of patients (88). This may be explained in part by the obser- diabetic nephropathy showed an inverse correlation between vation that decreased gelatinase activity in STZ-treated rats can MMP-3/TIMP-1 mRNA levels and matrix accumulation (74). be restored by insulin treatment (89). Glucose levels also may In addition, a marked decrease in MMP-2 mRNA expression indirectly influence matrix turnover, since glycated fetal bo- was detected in glomeruli of diabetic patients (75). Taken vine serum was shown to decrease matrix turnover by glomer- together, these findings suggest that matrix accumulation in ular epithelial cells (90), and glycated type IV collagen has diabetic nephropathy is due to increased matrix synthesis and been shown to be less degradable by MMP-3 and MMP-9 (91). decreased degradation, and that MMP may play a pivotal role. The need for tight glycemic control in diabetes is emphasized The mechanisms underlying this process have not yet been by a recent study showing that pancreas transplantation can completely elucidated. Both circulating and/or locally synthe- reverse glomerular lesions in patients with diabetic nephropa- sized growth factors and cytokines modulate MMP expression thy (92), even though other intrinsic factors that have not yet in diabetic nephropathy. We have shown that insulin-like been identified may play a role in this setting. growth factor-1 decreases MMP expression, and thus down- In addition, the genetic background may have a strong regulates collagen degradation in mesangial cells derived from influence on the incidence of renal complications in diabetes diabetic NOD mice (76,77). (93), and the level of MMP expression may be one of the The role of TGF-␤ in the pathogenesis of ECM accumula- determinants. STZ-treated Sprague Dawley rats developed di- tion remains controversial. TGF-␤ has been shown to upregu- abetic nephropathy and exhibited decreased metalloproteinase ␤ late MMP-2 (78). In a recent study in db/db mice, TGF- 1 levels. These nephropathy changes and altered MMP expres- levels in diabetic kidney cortex have been shown to be de- sion were not observed in spontaneously diabetic BB/DP and creased (79). It is not clear how this finding relates to previous STZ-treated BB/DR rats (71). Thus, MMP may be useful to observations of increased TGF-␤ levels in diabetic nephropa- identify patients at risk for developing progressive renal fail- ␤ ␤ thy (80,81). The role of TGF- 1 and TGF- -neutralizing pro- ure. teoglycans (82) in the pathogenesis of diabetic nephropathy In summary, progressive glomerulosclerosis in a variety of may have to be reevaluated (83). diseases, such as diabetic nephropathy, is characterized by a Oxidative stress (84) contributes to matrix accumulation profound shift in ECM turnover toward increased matrix ac- either directly due to inhibition of MMP-2 (85), or by inducing cumulation, leading to mesangial matrix expansion, decrease in a cytokine response (86,87). filtration area, and ultimately end-stage renal failure. Glomer- The detrimental role of hyperglycemia itself has been estab- ular MMP levels could determine the slope of progression and lished by the observation that glycemic control can prevent or the degree of glomerular scarring. Experimental data suggest J Am Soc Nephrol 11: 574–581, 2000 MMP in Renal Development and Disease 577 that this is a general theme in a variety of primarily noninflam- MMP and/or TIMP to further define the role of MMP in matory diseases associated with glomerulosclerosis. glomerulonephritis.

MMP in Glomerulonephritis MMP in Renal Development In inflammatory glomerular diseases, the findings are quite Both renal disease and kidney development are character- different with regard to MMP expression. Increased levels of ized by a high rate of ECM turnover, which may indicate that MMP are generally associated with disease activity and influx similar mechanisms are at work. During renal development, a of inflammatory cells, and both the level and the duration of constant remodeling of ECM is required to allow invasion and MMP elevation determine the extent of glomerular damage. branching of the ureteric bud in the metanephric mesenchyme, In mice with experimental lupus nephritis, MMP-1, -2, and which suggests a role for matrix-degrading enzymes. Nephro- -3 were shown to be increased (94), while an elevation of genesis is characterized by a complex interaction between MMP-2 and MMP-9 was observed in both anti-Thy1.1 ne- epithelium and mesenchyme (21,110–112). Since a differential phritic rats (78,95,96) and rats with passive Heymann nephritis spatiotemporal expression of MMP and TIMP has been shown (97). Increased MMP expression in Thy1.1 nephritis may be in the development of other branching organs (113), a similar partly mediated by growth factors released by invading acti- role of MMP and TIMP in renal organogenesis has been vated neutrophils and macrophages (98,99). Another possibil- proposed (114,115). In the developing kidney, MMP-2 mRNA ity is a permanent change in the phenotype of mesangial cells expression is limited to the mesenchyme. MMP-2 protein, due to the inflammatory process, since mesangial cells isolated however, has been found in immature nephron structures un- from nephritic animals maintain their altered phenotype in dergoing epithelial differentiation, where it colocalizes with vitro (100). Data from human studies also show that elevated MT-1-MMP, TIMP-2, and TIMP-3 (116,117). This has given MMP levels are associated with a highly active inflammatory rise to the hypothesis that the interaction between MMP-2, response associated with glomerular damage. Elevated levels MT-1-MMP, and TIMP-2 may be crucial for the interaction of MMP were found in various forms of glomerulonephritis in between mesenchyme and epithelium, facilitating branching of Japanese patients (101,102). the developing ureteric bud. This hypothesis is supported by Taken together, experimental data and findings from human the fact that treatment with MT-1-MMP antisense oligode- studies suggest that elevated glomerular MMP expression con- oxynucleotides inhibits the branching process (118), and that tributes to the disease process, and that increased MMP activity the expression of MMP-2 and MT-1-MMP is regulated in a correlates with structural glomerular damage. Unlike experi- temporal manner (117). A recent study showed that inhibition mental Thy1.1 nephritis in rats, which resolves spontaneously of MMP-2 by TIMP-2 strongly reduced the number of when only one dose is given, many forms of glomerulonephri- branches in the rat metanephros (119). It is unclear why only tis in humans progress to end-stage renal failure. In experi- treatment with an anti-MMP-9 antibody prevented ureteric bud mental nephritis, both dietary measures (103) and MMP inhi- branching in 11-d mouse kidneys, while an anti-MMP-2 anti- bition attenuate glomerular lesions (96), suggesting a role for body did not have a deleterious effect (22). Analysis of the MMP inhibitors in the treatment of acute glomerulonephritis kidney morphology in MMP-2- and MMP-9-deficient mice (96,104,105). Thus, future therapeutic approaches may include may help to clarify the role of the two gelatinases in renal targeting selected members of the MMP family and/or their organogenesis (48,120). However, other MMP, such as endogenous inhibitors. Additional studies will be needed, how- MMP-1, have also been shown to play a role in the branching ever, to establish the efficacy of this measure in preventing morphogenesis and may be modulated by growth factors such progressive renal failure. as TGF-␤ (121). Thus, MMP seem to play an important role in The most common form of nephrotic syndrome in adults is epithelium–mesenchyme interactions in renal development and membranous glomerulonephritis. A role for MMP in the alter- the determination of nephron number. A decrease in the total ation of basement membrane permeability has been postulated number of nephrons has been postulated to play a role in the by an uncontrolled study in patients with membranous glomer- development of chronic renal disease later in life (122–124). ulonephritis, which revealed elevated levels of TGF-␤ and Conditions known to reduce nephron number, such as malnu- collagenase activity in the urine (106). This notion is supported trition (125) or gentamicin nephrotoxicity (126), may be me- by the finding that MMP-9 expression by podocytes is in- diated by decreased fetal MMP expression. creased in a model of membranous nephropathy (97). In a In summary, the tight regulation of the MMP system is mouse model mimicking focal segmental glomerulosclerosis, essential for normal renal development. Although it may be characterized by the lack of Mpv17 gene expression leading to possible to counteract MMP dysregulation pharmacologically, persistently high levels of MMP-2, the authors found foot additional studies will be needed to elucidate the regulation of process flattening, heavy proteinuria, and ultimately severe MMP expression in the developing kidney under normal and glomerulosclerosis (107–109). However, the glomerular ex- pathologic conditions, so that the appropriate time and type of pression pattern of MMP and TIMP has not yet been studied in intervention can be determined. detail. 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