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Roderick J. Tan and Youhua Liu
Am J Physiol Renal Physiol 302:F1351-F1361, 2012. First published 4 April 2012;
doi: 10.1152/ajprenal.00037.2012
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Am J Physiol Renal Physiol 302: F1351–F1361, 2012.
First published April 4, 2012; doi:10.1152/ajprenal.00037.2012. Review
THE MATRIX METALLOPROTEINASES (MMPs) are a large family of proteolytic potential, MMPs are traditionally conceived as
zinc-dependent endopeptidases that are collectively capable of antifibrotic players in the development and progression of
proteolyzing all components of the extracellular matrix (ECM) chronic kidney diseases (CKD), in which tissue fibrosis is the
(15, 99). The first discovery of MMPs was originally reported common outcome. This assumption, however, has been chal-
by Gross and Lapiere (38) when they described collagenase lenged recently, and a new paradigm is emerging that MMPs
activity in metamorphosing tadpoles. Since then, the number of actually play a critical role in the initiation of fibrotic kidney
known MMPs as well as their characterized functions have disorders. Here, we review the biology of MMPs, with empha-
risen dramatically (83, 139). It is now accepted that MMPs sis on their role and potential mechanisms in the development
play a multitude of roles in regulating a diverse array of of kidney diseases.
biological processes such as embryonic development, tissue
homeostasis, tumorigenesis, and organ fibrogenesis (15, 97). Biology of MMPs
Initially thought to degrade only ECM proteins, MMPs are Structure and classification. All MMPs, with some modifi-
increasingly known to be able to cleave a wide variety of cations, share a core set of basic structural domains. As shown
substrates, which range from cell surface receptors and adhe- in Fig. 1, the prototype MMP consists of a prodomain, a
sion molecules to growth factors and cytokines. This broad catalytic domain, a hinge region, and a hemopexin-like domain
spectrum of substrates enables MMPs to be a critical player not (15, 87). As secreted proteins, MMPs are synthesized with a
only in regulating ECM remodeling but also in controlling signal peptide responsible for directing secretion out of the cell.
many cell behaviors such as cell proliferation, migration, The prodomain consists of a conserved cysteine residue that
differentiation, angiogenesis, and apoptosis (37, 83). Over the prevents binding and cleavage of the substrate, while the catalytic
last decade, thanks to the availability of many genetically domain contains a binding site comprised of three histidines that
modified mice (both knockout and transgenic) and specific coordinate with a single zinc and is responsible for the enzymatic
pharmacological inhibitors, our understanding of the biology activity of the protease. MMP-2 and -9 have a series of fibronectin
of MMPs in vivo has substantially evolved and improved. repeats in this domain as well. A flexible hinge region then
Many studies have provided significant insights into the exact separates the catalytic domain from a four-bladed propeller-
roles of specific MMPs in regulating physiological homeostasis shaped hemopexin domain. It is felt that substrate specificity as
and pathological disorders. well as endogenous inhibitor binding are influenced by speci-
MMPs are expressed in both developing and adult kidneys, ficities of each MMP’s catalytic and hemopexin domains (37,
and they are implicated in regulating nephron formation and 139). Some MMPs remain tethered to the cell via transmem-
the pathogenesis of kidney diseases, as nicely summarized brane and cytoplasmic domains at the C terminus. At least one
previously in a comprehensive review (15). In light of their MMP (MMP-23) has a type II transmembrane domain near the
N terminus and also possesses a cysteine-rich region and
Address for reprint requests and other correspondence: Y. Liu, Dept. of immunoglobulin-like domain (87, 139). The crystal structure
Pathology, Univ. of Pittsburgh, S-405 Biomedical Science Tower, 200 Lothrop of active human MMP-1 containing many of the domains
St., Pittsburgh, PA 15261 (e-mail: liuy@upmc.edu). described above is shown in Fig. 2.
http://www.ajprenal.org 1931-857X/12 Copyright © 2012 the American Physiological Society F1351
Review
F1352 MMPs IN KIDNEY DISEASES
MMP-1 Collagenase-1 Collagen I, II, III, entactin, perlectan, IGF-BP-2 and -3, pro-IL-1, IL-1 38
MMP-2 Gelatinase A Gelatin, collagen IV, V, XI, laminin, aggrecan, pro-TGF-, pro-TNF-␣, 18, 131
IGFBP-3 and -5
MMP-3 Stromelysin-1 Aggrecan, laminin, fibronectin, fibrinogen, MCP-1 to -4, pro-MMP-1, -3, -7, 56, 126
-8, -9, -13
MMP-7 Matrilysin Plasminogen, pro-␣-defensin, FasL, pro-TNF-␣, E-cadherin, syndecan, 45, 78, 99, 140
pro-MMPs
MMP-8 Collagenase-2 Collagen I-III, VII, X, aggrecan, fibronectin, pro-TNF-␣, IGF-BP, MCP-1, 136
angiotensin
MMP-9 Gelatinase B Gelatin, collagen IV, V, XI, pro-IL-8, Pro-TNF-␣, pro-TGF-, pro-MMP-2, 49, 146, 153
findings suggest that although the cysteine switch thiol is the kidney disease. Table 2 summarizes the effect of these MMP-
preferred site of oxidative alteration, at times of greater oxidant specific interventions in renal pathology.
production, the enzyme is inactivated, possibly preventing Acute kidney injury. Acute kidney injury (AKI) is usually
overactivity. Such fine-tuning of MMP activity by oxidative caused by exposure to ischemia-reperfusion injury or nephro-
stress underscores the complexity of MMP regulation. Whether toxins and is a major cause of morbidity and mortality (142).
such mechanisms play a role in renal pathology remains to be Urinary MMP-9, in combination with other markers, could
determined. serve as a biomarker of AKI (40). A wide variety of AKI
Natural inhibitors. MMP activity is regulated by a family of models have characterized an increase in the expression of
naturally occurring, endogenous inhibitors known as tissue inhib- MMP-2 and MMP-9 as well as MMP-7 (8, 11, 91). Although
itors of metalloproteinases (TIMPs). The four known TIMPs have methods to decrease MMP activity generally reduce injury in
varying specificities for different MMPs but collectively can the majority of experimental models, at least one study shows
inhibit all of them. Generally, TIMPs combine in 1:1 stoichiom- that MMP-9 knockouts did worse, due to a diminished anti-
etry with MMPs and associate with the catalytic and hemopexin apoptotic signaling through stem cell factor (Table 2).
domains to cause inhibition (87). However, TIMPs also partici- Diabetic nephropathy. Diabetic nephropathy is the most
pate in metalloproteinase activation, as in the case of TIMP-2- common cause of end-stage kidney disease in the industrialized
associated activation of MMP-2 in the presence of MT1-MMP. world and is characterized clinically by albuminuria and pro-
There is now evidence that TIMPs can participate in other non- gressive renal failure, and pathologically by mesangial expan-
traditional functions such as cell proliferation, apoptosis, and sion, glomerulosclerosis, tubular atrophy, and interstitial fibro-
angiogenesis, and that a role of MMPs is to modulate TIMP sis (87). Collectively, the majority of studies show increased
signaling via sequestering a limited pool of TIMPs (82, 87). MMP-2, MMP-8, and MMP-9 in the serum and urine from
diabetic patients (36, 60, 65, 108, 125, 126, 135). In fact, a
MMPs in Renal Pathology
positive correlation exists between degree of albuminuria and
While the temporal and spatial expression of MMPs in the levels of urinary MMP-9 (125). In addition, urinary excretion
kidney has not been completely characterized, numerous stud- of NGAL is concomitantly increased with MMP-9, which is
ies have demonstrated dysregulation of MMPs in a wide particularly intriguing since NGAL is not only a proposed
variety of kidney disorders. Figure 3 compiles the distribution biomarker of kidney injury but can aid in sustained activation
and expression profile of MMPs along the nephron in normal of MMPs (127). An elevated serum MMP-7 level may also be
and pathological conditions. Ample evidence also suggests that a biomarker, as it is inversely correlated with renal function in
MMPs could be potential targets for therapeutic intervention in proteinuric diabetic patients (5). Tubular expression of MMP-7
is induced in human kidney biopsies from patients with dia- MMP activity, particularly of MMP-2 and MMP-9, ameliorate
betic nephropathy, and its level is closely correlated with kidney lesions (107, 114, 144, 150), whereas in other models
-catenin abundance (45). Observations have also described maintenance of MMPs, namely, MMP-1 and in some cases
downregulation of MMP-1 and TIMPs, with upregulation of even MMP-9, is associated with improvement (see Table 2) (4,
membrane-type MMPs (21, 60, 108, 109). 34). Similarly contradictory, TIMP-3 was elevated in diabetes,
The role of MMPs in the pathogenesis of diabetic nephrop- but TIMP-3 null mice actually had worsened fibrosis and
athy is controversial and inconsistent. In addition, experimental increased activation of MMP-2 (55, 57). Collectively, these
models do not always recapitulate clinical findings, as recently data highlight the complexities of MMP pathobiology and the
reviewed (126). These contradictions could be caused by continued need for mechanistic studies.
differences in animal strains, samples obtained, and cell types Nondiabetic glomerular disease. MMP levels are altered in
examined, as well as the fact that diabetes treatment affects other nondiabetic glomerular diseases. Single nucleotide poly-
MMP expression (126). Some models show that decreased morphisms in MMP-14 confer risk for developing focal seg-
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