Matrix Metalloproteinase 9 Protects Mice from Anti–Glomerular Basement Membrane Nephritis through Its Fibrinolytic Activity

Lelongt, Brigitte; Bengatta, Soraya; Delauche, Madeleine; Lund, Leif R.; Werb, Zena; Ronco, Pierre

doi:10.1084/jem.193.7.793

Cited by 121 publications

(101 citation statements)

References 24 publications

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“…In addition, MMP-9 showed an enhanced expression in Heymann nephritis, a model of membranous nephropathy (45). It is interesting that MMP-9 may also be protective, as shown for the development of fibrin-induced glomerular damage (46). In this study, susceptibility to the accelerated model of anti-glomerular basement membrane nephritis was enhanced in MMP-9(Ϫ/Ϫ) compared with MMP-9(ϩ/ϩ) mice.…”

Section: Discussionmentioning

confidence: 59%

Angiotensin-Converting Enzyme Inhibition but not Angiotensin II Receptor Blockade Regulates Matrix Metalloproteinase Activity in Patients with Glomerulonephritis

Lods

Ferrari

Frey

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Equivalent long-term effects on the kidney are attributed to angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB). Nevertheless, it is unknown to which degree effects of these compounds on individual inflammatory mediators, including matrix metalloproteinases (MMP), are comparable. On the basis of structural and functional differences, it was hypothesized that ACEI and ARB differentially regulate MMP activity. In a randomized, prospective crossover trial, the effect of an ACEI (fosinopril; 20 mg/d) and of an ARB (irbesartan; 150 mg/d) on MMP activity was evaluated. Ten hypertensive patients with glomerulonephritis and normal or mildly reduced creatinine clearance were studied. MMP activity and tissue inhibitors of metalloproteinase (TIMP) levels were analyzed in serum and urine: without therapy, with ACEI, with ARB, and with both agents combined. Treatment periods continued for 6 wk separated by periods of 4 wk each without therapy. Untreated patients with glomerulonephritis displayed distinctively higher serum levels of MMP-2 but much lower MMP-1/-8/-9 concentrations compared with healthy control subjects. Immunohistology of MMP-2 and MMP-9 in kidney biopsy specimen was accordingly. However, these patients excreted higher amounts of MMP-2 and MMP-9 in urine than healthy control subjects, possibly reflecting ongoing glomerular inflammation. In patients with glomerulonephritis, ACEI significantly reduced overall MMP serum activity to 25%, whereas ARB did not show any effect. Activities of MMP-1/-2/-8/-9 were also significantly inhibited by fosinopril but not by irbesartan. Levels of TIMP-1/-2 remained unaffected. In conclusion, ACEI and ARB differentially regulate MMP activity, which may ultimately have consequences in certain types of MMP-dependent glomerulonephritis.Glomerular inflammatory diseases represent frequent and often difficult-to-treat causes of end-stage kidney failure. Hypertension and proteinuria are important independent determinants and risk factors for progression of these diseases (1). Therefore, these two conditions are prime targets for the therapy of all types of glomerulonephritis.Pharmacologic inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) has been particularly well demonstrated to treat high BP and proteinuria successfully (1). Moreover, the decline of kidney function occurring in diabetic as well as in nondiabetic glomerulopathies was greatly reduced by these agents in many investigations (2,3). Although ARB have only recently been introduced to common clinical use, several studies reported equivalent renoprotection for both classes of agents, ACEI and ARB (1). However, the issue of long-term effects with regard to the kidney is not yet fully resolved, and the identification of patient groups in which one of these agents demonstrates potential advances over the other one remains of pivotal clinical interest.Angiotensin II plays a key role...

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Section: Discussionmentioning

confidence: 59%

Angiotensin-Converting Enzyme Inhibition but not Angiotensin II Receptor Blockade Regulates Matrix Metalloproteinase Activity in Patients with Glomerulonephritis

Lods

Ferrari

Frey

et al. 2003

Journal of the American Society of Nephrology

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“…The same MMP can have different roles in different conditions. For example, MMP9 contributes to inflammation in mouse models of stroke, heart attack, Alzheimer's disease, some aspects of asthma and other lung inflammatory conditions, aortic aneurysms and autoimmune encephalomyelitis 9,106-110 ; however, it functions as an anti-inflammatory agent in models of inflammatory skin and kidney diseases 89,111,112 . Current data indicate that MMP12 contributes to emphysema 113,114 , whereas MMP3 and MMP9 contribute to skin inflammatory conditions 89,115 .…”

mentioning

confidence: 99%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

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2,521

2,180

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Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775-Ile776 or Gly775-Lys776 in native type I, II or III collagen molecules 3,4 . Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5 ). However, recent clinical data indicate that the relationship between § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6 ). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

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“…Indeed, some substrates show over 200-fold selectivity towards MMP-2 Kridel et al, 2001). (Morodomi et al, 1992;Okada et al, 1990) Native collagen type: I yes no (Aimes and Quigley, 1995) III yes no (Berton et al, 2000) IV yes yes (Morodomi et al, 1992) V yes yes (Morodomi et al, 1992) VII yes (Seltzer et al, 1989) X yes (Cole et al, 1993) XI yes (Smith et al, 1991) XVIII yes (Ferreras et al, 2000) Aggrecan yes yes (Fosang et al, 1992) BM-40/SPARC/ Osteonectin yes yes (Sasaki et al, 1997) Brevican yes no Decorin yes no (Imai et al, 1997) Elastin yes yes Entactin/nidogen no yes (Mayer et al, 1993;Sires et al, 1993) Fibrillin yes yes (Ashworth et al, 1999) Fibrin yes (Lelongt et al, 2001) Fibrinogen yes yes (Bini et al, 1996;Lelongt et al, 2001) Fibronectin yes no (Okada et al, 1990) Laminin yes yes (Giannelli et al, 1997;Morodomi et al, 1992) Link protein yes yes (Nguyen et al, 1993) NG2 proteoglycan yes (Larsen et al, 2003) Neurocan yes (Turk et al, 2001) Tenascin yes no (Siri et al, 1995) Vitronectin yes yes (Imai et al, 1995) α2-macroglobulin yes yes (Arbelaez et al, 1997) αB-crystallin yes (Starckx et al, 2003) Amyloid protein precursor yes (LePage et al, 1995) Big endothelin-1 yes yes (Fernandez-Patron et al, 2002) Calcitonin gene-related peptide (CGRP) yes (Fernandez-Patron et al, 2000) Complement protein C1q yes yes (Ruiz et al, 1999) Connective tissue-activating peptide-III (CTAP-III) yes (Van den Eph B1 tyrosine kinase receptor yes no Epithelial-cell derived neutrophil activating pept...…”

Section: Gelatinase Substratesmentioning

confidence: 99%