Developmental expression of meprin metalloprotease subunits in ICR and C3H/He mouse kidney and intestine in the embryo, postnatally and after weaning

Kumar, Janet M.; Bond, Judith S.

doi:10.1016/s0167-4781(01)00188-9

Cited by 24 publications

(20 citation statements)

References 35 publications

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“…However, the underrepresentation of meprin ␤ null mice in the F 2 population indicates that meprin ␤ is important for either embryonic development, implantation, or fertilization. Previous work demonstrated that meprin ␣ and ␤ are expressed in the kidney and intestine during embryogenesis (16). Furthermore, EST data indicate that meprin ␤ is expressed as early as the first blastocyst stage as well as in adult testis; this raises the possibility that meprin ␤ could be important for sperm maturation or function.…”

Section: Discussionmentioning

confidence: 98%

“…(i) Certain inbred strains of mice, such as C3H/He and CBA, do not express meprin ␣ in adult kidney and intestine, while all mouse strains tested express meprin ␤ in the adult and embryonic kidney and intestine; this indicates that meprin ␤ is more likely than meprin ␣ to be essential in adult mice (2,16). (ii) Linkage analysis has implicated meprin ␤ as a candidate gene for diabetic nephropathy in the Pima Indian population, a population in which 92% of end stage renal disease cases are attributed to diabetic nephropathy (12,23).…”

Section: Meprins (Meprin a [Ec 342418] And Meprin B [Ecmentioning

confidence: 99%

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Targeted Disruption of the Meprin β Gene in Mice Leads to Underrepresentation of Knockout Mice and Changes in Renal Gene Expression Profiles

Norman

Jiang

Han

et al. 2003

Molecular and Cellular Biology

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Meprins are multidomain zinc metalloproteases that are highly expressed in mammalian kidney and intestinal brush border membranes and in leukocytes and certain cancer cells. Mature meprins are oligomers of evolutionarily related, separately encoded ␣ and/or ␤ subunits. Homooligomers of meprin ␣ are secreted; oligomers containing meprin ␤ are plasma membrane associated. Meprin substrates include bioactive peptides and extracellular matrix proteins. Meprins have been implicated in cancer and intestinal inflammation. Additionally, meprin ␤ is a candidate gene for diabetic nephropathy. To elucidate in vivo functions of these metalloproteases, meprin ␤ null mice were generated by targeted disruption of the meprin ␤ gene on mouse chromosome 18q12. Analyses of meprin ␤ knockout mice indicated that (i) 50% fewer null mice are born than the Mendelian distribution predicts, (ii) null mice that survive develop normally and are viable and fertile, (iii) meprin ␤ knockout mice lack membrane-associated meprin ␣ in kidney and intestine, and (iv) null mice have changes in renal gene expression profiles compared to wild-type mice as assessed by microarray analyses. Thus, disruption of the meprin ␤ allele in mice affects embryonic viability, birth weight, renal gene expression profiles, and the distribution of meprin ␣ in kidney and intestine.Meprins (meprin A [EC 3.4.24.18] and meprin B [EC 3.4.24.63]), metalloproteases of the astacin family, comprise approximately 5% of kidney brush border membrane protein in mice (2, 3). They are also expressed in intestinal brush border membranes, in leukocytes, and in certain epithelial cancer cells (17,21). Various growth factors, cytokines, and extracellular matrix proteins are substrates for meprin in vitro; among the best substrates are gastrin, gastrin-releasing peptide, monocyte chemoattractant protein-1, osteopontin, and laminin (1, 15). The nature of these substrates and the expression patterns of the subunits in acute renal failure, intestinal disease, and cancerous cells implicate meprins in the regulation of growth, inflammation, cancer cell metastasis, and matrix remodeling (5,15,17,18,21,33).The meprin subunits, ␣ and ␤, associate to form homo-or heterooligomers (19). Although the subunits are encoded by distinct genes on different chromosomes (Mep1␣ on chromosome 6 in humans and 17 in mice and Mep1␤ on chromosome 18 in both species), under some circumstances there is coordinate regulation of the expression of the genes that results in heterooligomeric protein complexes (4). Meprin ␣ and ␤ subunits are 42% identical at the amino acid level and share the same domain structure, except that meprin ␣ contains an inserted (I) domain which is not present in meprin ␤ (20). The I domain directs the proteolytic cleavage of meprin ␣ during maturation in the endoplasmic reticulum so that the bulk of the subunit is released from the membrane. The consequence of the cleavage is that meprin ␣ is secreted unless it interacts with membrane-associated meprin ␤. In vivo, meprin ␣ is secreted as ...

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Section: Discussionmentioning

confidence: 98%

Section: Meprins (Meprin a [Ec 342418] And Meprin B [Ecmentioning

confidence: 99%

Targeted Disruption of the Meprin β Gene in Mice Leads to Underrepresentation of Knockout Mice and Changes in Renal Gene Expression Profiles

Norman

Jiang

Han

et al. 2003

Molecular and Cellular Biology

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“…The use of MMP inhibitors with differing selectivities for MMP-related enzymes has identified a novel role for metalloproteases in controlling lymphocyte transendothelial migration (53) and in blocking T cell migration across synthetic basement membranes in vitro (54). Meprin B of the ␤ homo-oligomeric form and meprin A of the ␣ and ␤ hetero-oligomeric form are localized to apical brush border of the renal and intestinal proximal tubule epithelium (34) (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

Mannan-Binding Protein Blocks the Activation of Metalloproteases Meprin α and β

Hirano¹,

Yong²,

Kawasaki

et al. 2005

The Journal of Immunology

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Mannan-binding protein (MBP) is a C-type serum lectin that is known to be a host defense factor involved in innate immunity, and recognizes mannose, fucose, and N-acetylglucosamine residues. Although some exogenous MBP ligands have been reported, little is known about its endogenous ligands. In the present study, we found that endogenous MBP ligands are highly expressed in the brush border epithelial cells of kidney-proximal tubules by immunohistochemistry, and both meprin α and β (meprins), as novel endogenous MBP ligands, have been identified through affinity chromatography and mass spectrometry. Meprins are membrane-bound and secreted zinc metalloproteases extensively glycosylated and highly expressed in kidney and small intestinal epithelial cells, leukocytes, and certain cancer cells. Meprins are capable of cleaving growth factors, extracellular matrix proteins, and biologically active peptides. Deglycosylation experiments indicated that the MBP ligands on meprins are high mannose- or complex-type N-glycans. The interaction of MBP with meprins resulted in significant decreases in the proteolytic activity and matrix-degrading ability of meprins. Our results suggest that core N-linked oligosaccharides on meprins are associated with the optimal enzymatic activity and that MBP is an important regulator for modulation of the localized meprin proteolytic activity via N-glycan binding. Because meprins are known to be some of the major matrix-degrading metalloproteases in the kidney and intestine, MBP, which functions as a natural and effective inhibitor of meprins, may contribute, as a potential therapeutic target, to tumor progression by facilitating the migration, intravasation, and metastasis of carcinoma cells, and to acute renal failure and inflammatory bowel diseases.

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“…Meprin B and the ␣ and ␤ hetero-oligomeric form of meprin A are localized to the apical brush border of the intestinal and renal proximal tubule epithelium (5,10). In addition, meprin is likely to have a role in leukocyte biology in the intestine, as Lottaz et al (11) detected the expression of meprin ␣ and ␤ transcripts in ϳ30% of the CD45 ϩ leukocytes in the lamina propria of the inflamed human intestine.…”

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confidence: 99%

Deletion of the Mouse Meprin β Metalloprotease Gene Diminishes the Ability of Leukocytes to Disseminate through Extracellular Matrix

Crisman

Zhang

Norman³

et al. 2004

The Journal of Immunology

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Meprins are metalloendopeptidases expressed by leukocytes in the lamina propria of the human inflamed bowel, that degrade extracellular matrix proteins in vitro implicating them in leukocyte transmigration events. The aims of these studies were to 1) examine the expression of meprins in the mouse mesenteric lymph node, 2) determine whether macrophages express meprins, and 3) determine whether deletion of the meprin β gene (Mep-1β) mitigated the ability of leukocytes to disseminate through extracellular matrix in vitro. These studies show that meprin α and β are expressed in leukocytes of the mouse mesenteric lymph node, and meprin α, but not β, decreased during intestinal inflammation. Deletion of Mep-1β gene decreased the ability of leukocytes to migrate through matrigel compared with wild-type leukocytes. Meprin β, but not α, was detected in cortical and medullary macrophages of the lymph node. Thus overall, meprin β is expressed by leukocytes in the draining lymph node of the intestine, regardless of the inflammatory status of the animal, and is likely to contribute to leukocyte transmigration events important to intestinal immune responses. Thus, the expression of meprins by leukocytes of the intestinal immune system may have important implications for diseases such as inflammatory bowel diseases, which are aggravated by leukocyte infiltration.

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Developmental expression of meprin metalloprotease subunits in ICR and C3H/He mouse kidney and intestine in the embryo, postnatally and after weaning

Cited by 24 publications

References 35 publications

Targeted Disruption of the Meprin β Gene in Mice Leads to Underrepresentation of Knockout Mice and Changes in Renal Gene Expression Profiles

Targeted Disruption of the Meprin β Gene in Mice Leads to Underrepresentation of Knockout Mice and Changes in Renal Gene Expression Profiles

Mannan-Binding Protein Blocks the Activation of Metalloproteases Meprin α and β

Deletion of the Mouse Meprin β Metalloprotease Gene Diminishes the Ability of Leukocytes to Disseminate through Extracellular Matrix

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