![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
Xiaoli Han,1 Thomas L. Saunders,2 and Judith S. Bond1*
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, Hershey, Pennsylvania 17033-0850,1 Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 481092
Received 29 July 2002/ Returned for modification 10 September 2002/ Accepted 7 November 2002
 |
ABSTRACT |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and/or ß subunits. Homooligomers of meprin are secreted; oligomers containing meprin ß are plasma membrane associated. Meprin substrates include bioactive peptides and extracellular matrix proteins. Meprins have been implicated in cancer and intestinal inflammation. Additionally, meprin ß is a candidate gene for diabetic nephropathy. To elucidate in vivo functions of these metalloproteases, meprin ß null mice were generated by targeted disruption of the meprin ß gene on mouse chromosome 18q12. Analyses of meprin ß 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 ß 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 ß allele in mice affects embryonic viability, birth weight, renal gene expression profiles, and the distribution of meprin in kidney and intestine. |
INTRODUCTION |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The meprin subunits, and ß, 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 Mep1ß 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 ß 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 ß (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 ß. In vivo, meprin is secreted as a homooligomer and is also found as a heterooligomer at the plasma membrane in association with meprin ß, a type I transmembrane protein (10, 20).
Meprin ß was chosen for targeted disruption based on the following. (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 ß in the adult and embryonic kidney and intestine; this indicates that meprin ß is more likely than meprin to be essential in adult mice (2, 16). (ii) Linkage analysis has implicated meprin ß 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). (iii) Meprins have been implicated in the progression of pathology in renal ischemia and reperfusion, in ureteral obstruction, and in Alport's syndrome (24, 26, 32, 33). (iv) Lastly, meprin ß associates with meprin to maintain it at the cell surface; thus, in the absence of meprin ß the localization of meprin to the apical plasma membrane could be altered. Due to the consistent expression of meprin ß and its implication in disease, it was chosen as a target for disruption. The work reported here details the first characterization of meprin ß knockout mice.
|
MATERIALS AND METHODS |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Genotyping. Tail biopsies were digested overnight with agitation at 42°C with 6 U of proteinase K in 0.4 ml of buffer (50 mM Tris [pH 7.5], 100 mM EDTA, 125 mM NaCl, and 1% sodium dodecyl sulfate). A saturated NaCl solution (200 µl) was added to the digested samples. Samples were vortexed and then centrifuged for 15 min at 16,000 x g. The DNA was then ethanol precipitated from the resulting supernatant. Southern blot and PCR analyses were used to determine genotype. PCR primers 5'-GACTTCAAGCCTTGGTCCGGAG-3' and 5'-CCTGGCTGAATCCTGTCCC-3' generate a 2.2-or 3.7-kb amplicon for wild-type and knocked-out alleles, respectively. XbaI was used to digest 10 µg of DNA for Southern blotting. A 740-bp probe corresponding to exon 8 through exon 9 detects wild-type (8.4-kb) and disrupted (4.0-kb) alleles (Fig. 1B).
Immunohistochemistry.
Tissues were fixed in methyl Carnoy's solution (60% methanol, 30% chloroform, 10% acetic acid), embedded in paraffin wax, and thin sectioned (5 µm). An avidin-biotin blocking kit (Vector Laboratories) was used to block background contributed by endogenous biotin or biotin-binding proteins. Background Buster (Accurate Chemical & Scientific Corp.) was then used as a general blocking agent. Polyclonal rabbit anti-recombinant meprin or ß served as the primary antibody. Preimmune rabbit serum was used in place of primary antibody for negative controls. Biotinylated goat anti-rabbit immunoglobulin G (heavy plus light chains) at a final concentration of 7.5 µg/ml (Vector Laboratories) served as the secondary antibody. Sections were washed and then incubated with Vectastain ABC Elite reagents (Vector Laboratories). 3,3'-Diaminobenzidine (1 mg/ml) in Tris (pH 7.6) with 8.5% hydrogen peroxide was applied to all sections. Sections were counterstained with 1% methyl green, rinsed in 100% ethanol, submerged in xylene, and mounted with Permount (Fisher). Digital photographs were taken with a Nikon Eclipse E600 microscope.
Microarray. Kidneys from second filial generation (F2) adult male wild-type (n = 3), heterozygous (n = 3), and knockout (n = 4) mice of a mixed C57BL/6J x Sv129 background were individually homogenized in 4 ml of TRIzol (Invitrogen). The preparation of total RNA and the subsequent labeling, fragmentation, and hybridization steps were performed according to the protocols issued by Affymetrix.
In short, total RNA (8 µg) was reverse transcribed with Superscript II (Invitrogen) by using a high-pressure liquid chromatography-purified oligo(dT)24 primer encoding a T7 RNA polymerase promoter site. Double-stranded cDNA was then purified by phenol-chloroform extraction. The DNA was then ethanol precipitated from the aqueous phase, and the precipitate was air dried. All of the obtained cDNA was subjected to in vitro transcription labeling with biotinylated ribonucleotides by using the BioArray High Yield RNA transcript labeling kit (Enzo Diagnostics, Inc.). The resulting labeled RNA was purified by using RNeasy columns (Qiagen) and then quantified. Labeled RNA (20 µg) was fragmented for chip hybridization. Completeness of fragmentation was verified by gel electrophoresis of an aliquot of sample. Fragmented RNA (15 µg) was combined in hybridization buffer with BioB (1.5 pM), BioC (5 pM), BioD (25 pM), cre (100 pM), and B2 oligonucleotide (50 pM) hybridization controls, herring sperm DNA (0.1 mg/ml), and acetylated bovine serum albumin (0.5 mg/ml) (Affymetrix). Test3 chips (Affymetrix) were used to confirm that labeled RNA was properly fragmented and labeled and that 5', middle, and 3' portions of transcripts were represented. MG-U74Av2 oligonucleotide probe array chips (Affymetrix) were hybridized with 200 µl of the RNA mixture for 16 h at 45°C with rotation at 60 rpm. Arrays were washed and stained according to protocols utilized by the GeneChip Fluidics Station 400 (Affymetrix). Arrays were scanned and then scaled to an average intensity of 500 and analyzed with Microarray Suite 5.0. Chip files from Microarray Suite 5.0 were entered into a database by using Micro Database 3.0. This database was then analyzed by using Data Mining Tools 3.0 (Affymetrix). The average signal intensity and average fold change were analyzed for statistically significant changes (P < 0.05) by t test analysis.
Western blots of brush border membrane-enriched fractions and urinary meprin.
Renal brush border-enriched fractions were isolated as previously described (29). Total protein of the enriched fractions was determined by using the Bio-Rad Bradford dye standard assay (Bio-Rad). Samples were subjected to 7.5% polyacrylamide gel electrophoresis under reducing and denaturing conditions. Primary antibodies were polyclonal rabbit anti-recombinant meprin or ß. Secondary antibodies were sheep anti-rabbit immunoglobulin G conjugated to horseradish peroxidase.
To determine urinary meprin protein levels, urine samples from meprin ß null and wild-type mice were analyzed by Western blotting. Equal urinary creatinine was loaded onto polyacrylamide gels for each sample being compared. Since urine creatinine secretion is constant for an individual over 24 h, normalizing urine samples based on urine creatinine allows for comparative analyses among different animals. Sample normalization is essential because urine samples collected from different individuals may not be equal in volume and/or concentration (6, 9). Sample normalization using urine creatinine values is based on the assumption that the animals being compared have similar 24-h creatinine secretion. This is a valid assumption for this study because serum creatinine levels of meprin ß null and wild-type mice are not statistically different. Meprin band densities were determined by using NIH Image software. For analyses of urinary meprin and brush border membrane meprin and meprin ß, samples were obtained from individual age- and sex-matched animals. The blots shown are representative of data observed for at least five different animals per genotype.
Urine and serum analyses. Urine was collected from animals into sterile microcentrifuge tubes by bladder massage. For analyses of blood urea nitrogen (BUN), total serum protein, serum albumin, serum creatinine, serum glucose, and serology, blood was collected from the vena cava of ether-anesthetized mice. Chemstrip 10 SG dip sticks (Roche) were used for semiquantitative analysis of urinary pH, protein, nitrite, glucose, ketones, urobilinogen, bilirubin, blood, leukocytes, and specific gravity. Urine and serum creatinine levels were measured by using the Infinity Creatinine Assay (Sigma Diagnostics). Total urinary protein was measured by using the Bio-Rad Bradford dye standard assay. Mice can become pathologically proteinuric; under normal circumstances serum proteins are not present in murine urine, while smaller proteins such as the major urinary proteins are typically abundant in mouse urine (6). Serum albumin was determined by using the Sigma Diagnostics albumin reagent. BUN was measured by using the BUN rate reagent (Sigma Diagnostics).
RT-PCR. Total RNA isolated from mouse kidney by using TRIzol (Invitrogen) was subjected to reverse transcriptase PCR (RT-PCR) with the Superscript One-Step RT-PCR kit (Invitrogen). The amount of amplicon at various cycles was analyzed by using integrated band density data obtained with the Stratagene Eagle-Eye II system equipped with Eagle-Sight software. Glyceraldehyde-3-phosphate dehydrogenase was amplified as a control. For amplification of TRAF-6, the following primers were used: sense primer 5'-GGA AGA TTG GCA AGT TTG GGA TGC-3' and antisense primer 5'-AGT ACA TGG ACG CTA CAC CCC CG-3'.
Statistical analysis.
For analysis of genotype distributions of the F2 population, a chi-square (
2) analysis was performed on data obtained from F1 heterozygous crosses. For all other analyses, the unpaired, two-tailed t test was used; P values of <0.05 at a confidence interval of 95% were considered significant.
|
RESULTS |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2) analysis revealed that the meprin ß null mice (ß-/-) are underrepresented (P = 0.001) in the F2 population (Table 1). Mendelian genetics predicts that 25% of the animals born should be meprin ß null; however, only 12% of the animals born were homozygous null. Postnatal morbidity is unlikely to account for the discrepancy in the number of meprin ß null pups born, as all pups were counted on the day of birth as well as every day thereafter until they were genotyped at 21 days.
|
|
|
|
and ß mRNA expression and protein localization.
RT-PCR analyses of kidney RNA revealed that meprin ß mRNA was absent in knockout mice, as expected, and present at approximately half the wild-type level in ß+/- mice; meprin mRNA levels in the kidney and intestine were found to be similar among the three genotypes (data not shown). Microarray analyses confirmed that kidney meprin mRNA levels were not statistically different among the three genotypes and that meprin ß was absent in the knockout animals and present in heterozygous samples at half the level seen in wild-type mouse kidney (Table 4). Based on signal intensity values from microarray analyses, both meprin and meprin ß exhibit signal intensity levels indicative of abundant expression in wild-type kidney, as predicted by previous studies of kidney meprin protein.
|
nor meprin ß was membrane associated in these tissues in the adult animal (Fig. 3). In meprin ß heterozygous and meprin ß wild-type animals there was brown staining evident on the apical membranes of intestinal villi, indicating the presence of meprin and ß (Fig. 3). Staining for meprin subunits in kidney sections from the three genotypes was similar to that seen for intestinal sections; the apical membranes of kidney proximal tubule cells from heterozygous and wild-type mice stained positively for meprin , while kidney sections from meprin ß null mice did not exhibit membrane-associated meprin or meprin ß (Fig. 4). Quantitative Western blotting for meprin and ß protein in kidney brush border-enriched fractions from wild-type and heterozygous mice demonstrated that when a single meprin ß allele is disrupted, the commensurate halving of the ß protein at the membrane is concomitant with the presentation of half as much meprin on the brush border membrane (Fig. 5). As expected, neither meprin nor meprin ß was detectable in renal brush border fractions from meprin ß knockout mice.
|
|
|
protein levels and the meprin mRNA levels. Membrane-associated meprin is not detected in meprin ß knockout animals, while the meprin mRNA levels are not statistically decreased compared to those in wild-type or heterozygous mice. This difference is explained by the observation that meprin is secreted into the urine at greater levels in meprin ß knockout mice than in wild-type animals. Semiquantitative Western blots showed that on average meprin ß knockout animals have approximately twice the amount of urinary meprin as wild-type mice (Fig. 6). Urinary meprin subunits from knockout and wild-type animals form oligomeric complexes (from dimers to dodecamers) as evidenced by size exclusion chromatography (data not shown). Additionally, urinary meprin is secreted primarily as an activatable proprotein in both knockout and wild-type animals.
|
|
|
DISCUSSION |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and ß are expressed in the kidney and intestine during embryogenesis (16). Furthermore, EST data indicate that meprin ß is expressed as early as the first blastocyst stage as well as in adult testis; this raises the possibility that meprin ß could be important for sperm maturation or function. (WashU-HHMI Mouse EST Project, db EST Id 1337387 and EST Id 3378734, at www.ncbi.nlm.nih.gov). The microarray data here revealed that two genes, which are expressed in testis (sperm tail-associated protein and testis-specific gene-1), are increased in expression in the kidney in the absence of meprin ß. It is possible that the expression of these genes is also altered in testis in the absence of meprin ß and could thereby affect sperm function. The EST information is consistent with observations that several astacin family members are important in the early development of mammals and in hardening of the chorion in oviparous species (3, 27). In mice, implantation occurs 4 to 5 days following fertilization; for successful implantation to occur, the zona pellucida must be shed (28). Implantation is coupled with a surge in progesterone levels; this surge could induce meprin ß expression, as it has been shown that meprin ß expression is induced by glucocorticoids (11). If meprin ß is important for implantation, then one may predict that litter sizes of meprin ß null animals would be small compared to litter sizes of wild-type mice. While the average litter sizes of knockout and wild-type mice were not statistically different, 75% of meprin ß knockout litters were smaller than the average wild-type litter.
The litter sizes of the heterozygous F1 crosses were not statistically different from those of the wild-type crosses. One may expect that if approximately 10% of the F2 population is dying in utero, a concomitant decrease in the litter sizes of heterozygous F1 crosses compared to wild-type crosses would be observed. There are two possible explanations as to why this was not observed. The first is that for a 10% difference in litter sizes to be statistically significant, a very large number of litters must be observed. The second is that if the in utero discrepancy arises preimplantation, then wild-type or heterozygous blastocysts could implant and a smaller litter size may not be fully realized. This compensatory implantation would not occur in homozygous null crosses, since there would not be wild-type and heterozygous blastocysts present to implant.
With respect to postnatal growth, it was observed that meprin ß knockout pups weighed more than wild-type pups at birth. Meprins are known to cleave various peptide hormones, such as parathyroid hormone, -melanocyte-stimulating hormone, insulin B chain, gastrin, and gastrin-releasing peptide, in vitro; thus, alterations in peptide hormone degradation in meprin ß null mice may have an impact on fetal growth (1). Furthermore, maternal circulating glucose levels during pregnancy can influence birth weight; high maternal glucose levels have been correlated with increased birth weights (14, 26). While circulating glucose levels in adult, nonpregnant meprin ß knockout and wild-type mice did not appear to be statistically different, it is possible that during pregnancy circulating glucose levels differ between the genotypes and consequently have an impact on fetal growth. Additionally, meprin ß knockout female pups weighed more at weaning (21 days) than wild-type female pups, while differences among male pups were not observed. This observation implies that meprin ß differentially affects growth of males and females in the early postnatal stage.
The data here also demonstrate that the presence of meprin ß is obligatory for meprin to be membrane associated in the kidney and intestine. The most obvious implication of meprin localization being altered upon the disruption of the meprin ß gene is that under normal conditions meprin is not likely to appreciably interact with other membrane proteins in the kidney or intestine. Additionally, halving of the amount of meprin ß on the kidney brush border is accompanied by halving of the amount of meprin on the brush border, indicating that the interaction of meprin with meprin ß appears to have a regulated stoichiometry of oligomerization in vivo. These observations are consistent with previous data on the oligomerization of meprins (19). Meprin mRNA expression is not altered when the meprin ß gene is disrupted. Allelic dose compensation for meprin ß was not observed; in meprin ß heterozygous mice, a single functional copy of the meprin ß gene is insufficient to restore kidney meprin ß expression to the wild-type level.
While meprin is not detected on the apical membranes of renal proximal tubule cells in meprin ß null mice, it is clear that meprin is still apically targeted in these cells, since it is secreted into the urine. The observation that urinary meprin from both wild-type and meprin ß null mice is predominantly a zymogen is possibly a protective mechanism, since active meprin has been shown to be cytotoxic in vivo and in vitro (5). Characterizing the localization and expression of meprin in the meprin ß null mice is important, since in certain disease states the expression and localization of meprin is altered. For example, in colon cancer and renal ischemia-reperfusion injury, the localization of meprins is altered; a basolateral versus apical distribution is observed (18, 35). It has been proposed that the redistribution of meprins to the basolateral surface exacerbates injury.
Linkage analysis of the Pima Indian population by Imperatore et al. identified meprin ß as a candidate gene for diabetic nephropathy. For the Pima Indian study, the level of proteinuria of study participants was used as an assessment of renal function (12). Analyses of urine protein/urine creatinine level ratios of wild-type and meprin ß knockout mice did not reveal any statistical differences. Likewise, additional markers of kidney function, such as BUN and serum creatinine levels, were not statistically changed between the genotypes. It is possible, however, that a difference in renal function may be observed if diabetes is induced in these mice or in response to a renal stress. In several models of kidney disease, such as experimental hydronephrosis, toxin-induced nephrosis, and collagen IV 3 knockout mice (which develop Alport's syndrome), meprin ß expression is decreased (24, 25, 32, 33). Additionally, it is known that interstitial fibrosis, which characterizes the aforementioned renal diseases, is accompanied by alterations in various metalloproteinase activities as well as changes in metalloprotease inhibitors (8, 31). It has been suggested that decreases in metalloproteinases such as meprin can lead to tissue damage due to a reduced capacity to turn over or remodel basement membranes and extracellular matrix components (24, 33). Furthermore, the capacity of meprins to degrade certain cytokines implicates these metalloproteases in inflammation.
Assessing the response of meprin ß null mice to the various renal challenges will be important, especially in the context of evidence presented here, in that renal gene expression profiles are changed upon disruption of the meprin ß gene. Based on the types of renal gene expression changes that were observed, it is possible that meprins affect or interact with signaling proteins or other proteins at the cell surface that are involved in cell growth and the immune response. Such an interaction could be direct or indirect. The most dramatic changes in gene expression in meprin ß null kidneys arise for genes related to the cell growth and cell cycle processes and the immune system. These observations may relate to the ability of meprins to degrade various growth factors and to the point that meprins are expressed by certain cancer cells and leukocytes (17, 18, 21). Additionally, changes in the expression of TRAF-6 and Toll-like receptor-6 have implications with respect to the activation of c-Jun N-terminal kinase and NF-
B (7, 30).
This work has demonstrated that meprins are likely to be involved in development and growth. Furthermore, it has provided a baseline for future studies of the meprin ß null mice. It has also called into question the necessity for meprin ß in normal adult mice. Lastly, several genes related to the immune response and to cell growth have been identified as possible genetic compensation factors for disruption of the meprin ß gene. Further studies, including physiological challenges to the meprin ß knockout mice, are necessary to elucidate the in vivo function of meprins and their roles in disease states such as end stage renal disease and cancer.
|
ACKNOWLEDGMENTS |
|---|
This work was supported by NIH grants DK54625 and DK19691 (to J. S. Bond). The equipment and software for the microarray and immunohistochemistry analyses are supported by NIH grant CA40145 (to G. Clawson).
|
FOOTNOTES |
|---|
Present address: R & D Systems Inc., Minneapolis, MN 55413.
|
REFERENCES |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2. Bond, J. S., and R. J. Beynon. 1986. Meprin: a membrane-bound metallo-endopeptidase Curr. Top. Cell Reg. 28:263-290.
3. Bond, J. S., and R. J. Beynon. 1995. The astacin family of metalloendopeptidases. Protein Sci. 4:1247-1261.[Abstract]
4. Bond, J. S., K. Rojas, J. Overhauser, H. Y. Zoghbi, and W. Jiang. 1995. The structural genes, MEP1A and MEP1B, for the alpha and beta subunits of the metalloendopeptidase meprin map to human chromosomes 6p and 18q, respectively. Genomics 25:300-303.[CrossRef][Medline]
5. Carmago, S., S. V. Shah, and P. D. Walker. 2002. Meprin, a brush-border enzyme, plays an important role in hypoxic/ischemic acute renal tubular injury in rats. Kidney Int. 61:959-966.[CrossRef][Medline]
6. Chen, A., C. H. Wei, L. F. Sheu, S. L. Ding, and W. H. Lee. 1995. Induction of proteinuria by adriamycin or bovine serum albumin in the mouse. Nephron 69:293-300.[Medline]
7. Chung, J. Y., Y. C. Park, H. Ye, and H. Wu. 2002. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J. Cell Sci. 115:679-688.
8. Eddy, A. A., H. Kim, J. Lopez-Guisa, T. Oda, and P. D. Soloway. 2000. Interstitial fibrosis in mice with overload proteinuria: deficiency of TIMP-1 is not protective. Kidney Int. 58:618-628.[CrossRef][Medline]
9. Ginsberg, J. M., B. S. Chang, R. A. Matarese, and S. Garella. 1983. Use of single voided urine samples to estimate quantitative proteinuria. N. Engl. J. Med. 309:1543-1546.[Abstract]
10. Grunberg, J., E. Dumermuth, J. A. Eldering, and E. E. Sterchi. 1993. Expression of the alpha subunit of PABA peptide hydrolase (EC 3.4.24.18) in MDCK cells. Synthesis and secretion of an enzymatically inactive homodimer. FEBS Lett. 335:376-379.[CrossRef][Medline]
11. Henning, S. J., T. J. Oesterreicher, D. E. Osterholm, D. Lottaz, D. Hahn, and E. E. Sterchi. 1999. Meprin mRNA in rat intestine during normal and glucocorticoid-induced maturation: divergent patterns of expression of alpha and beta subunits. FEBS Lett. 462:368-372.[CrossRef][Medline]
12. Imperatore, G., W. C. Knowler, R. G. Nelson, and R. L. Hanson. 2001. Genetics of diabetic nephropathy in the Pima Indians. Curr. Diabetes Rep. 1:275-281.
13. Jiang, W., J. M. Kumar, G. L. Matters, and J. S. Bond. 2000. Structure of the mouse metalloprotease meprin beta gene (Mep1b): alternative splicing in cancer cells. Gene 248:77-87.[CrossRef][Medline]
14. Jovanovic-Peterson, L., C. M. Peterson, G. F. Reed, B. E. Metzger, J. L. Mills, R. H. Knopp, and J. H. Aarons. 1991. Maternal postprandial glucose levels and infant birth weight: the Diabetes in Early Pregnancy Study. Am. J. Obstet. Gynecol. 164:103-111.[Medline]
15. Kaushal, G. P., P. D. Walker, and S. V. Shah. 1994. An old enzyme with a new function: purification and characterization of a distinct matrix-degrading metalloproteinase in rat kidney cortex and its identification as meprin. J. Cell Biol. 126:1319-1327.
16. Kumar, J. M., and J. S. Bond. 2001. Developmental expression of meprin metalloprotease subunits in ICR and C3H/He mouse kidney and intestine in the embryo, postnatally and after weaning. Biochim. Biophys. Acta 1518:106-114.[Medline]
17. Lottaz, D., D. Hahn, S. Müller, C. Müller, and E. E. Sterchi. 1999. Secretion of human meprin from intestinal epithelial cells depends on differential expression of the alpha and beta subunits. Eur. J. Biochem. 259:496-504.[Medline]
18. Lottaz, D., C. A. Maurer, D. Hahn, M. W. Buchler, and E. E. Sterchi. 1999. Nonpolarized secretion of human meprin alpha in colorectal cancer generates an increased proteolytic potential in the stroma. Cancer Res. 59:1127-1133.
19. Marchand, P., J. Tang, and J. S. Bond. 1994. Membrane association and oligomeric organization of the alpha and beta subunits of mouse meprin A. J. Biol. Chem. 269:15388-15393.
20. Marchand, P., J. Tang, G. D. Johnson, and J. S. Bond. 1995. COOH-terminal proteolytic processing of secreted and membrane forms of the alpha subunit of the metalloprotease meprin A. Requirement of the I domain for processing in the endoplasmic reticulum. J. Biol. Chem. 270:5449-5456.
21. Matters, G. L., and J. S. Bond. 1999. Expression and regulation of the meprin beta gene in human cancer cells. Mol. Carcinog. 25:169-178.[CrossRef][Medline]
22. Nagy, A., J. Rossant, R. Nagy, W. Abramow-Newerly, and J. C. Roder. 1993. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl. Acad. Sci. USA 90:8424-8428.
23. Nelson, R. G., J. M. Newman, W. C. Knowler, M. L. Sievers, C. L. Kunzelman, D. J. Pettitt, C. D. Moffett, S. M. Teutsch, and P. H. Bennett. 1988. Incidence of end-stage renal disease in type 2 (non-insulin-dependent) diabetes mellitus in Pima Indians. Diabetologia 31:730-736.[CrossRef][Medline]
24. Ricardo, S. D., J. S. Bond, G. D. Johnson, J. Kaspar, and J. R. Diamond. 1996. Expression of subunits of the metalloendopeptidase meprin in renal cortex in experimental hydronephrosis. Am. J. Physiol. 270:F669-F676.
25. Sampson, N. S., S. T. Ryan, D. A. Enke, D. Cosgrove, V. Koteliansky, and P. Gotwals. 2001. Global gene expression analysis reveals a role for the alpha 1 integrin in renal pathogenesis. J. Biol. Chem. 276:34182-34188.
26. Scholl, T. O., M. Sowers, X. Chen, and C. Lenders. 2001. Maternal glucose concentration influences fetal growth, gestation, and pregnancy complications. Am. J. Epidemiol. 154:514-520.
27. Shibata, Y., T. Iwamatsu, Y. Oba, D. Kobayashi, M. Tanaka, Y. Nagahama, N. Suzuki, and M. Yoshikuni. 2000. Identification and cDNA cloning of alveolin, an extracellular metalloproteinase, which induces chorion hardening of medaka (Oryzias latipes) eggs upon fertilization. J. Biol. Chem. 275:8349-8354.
28. Snell, G. D., and L. C. Stevens. 1966. Early Embryology, p. 205-246. In E. L. Green (ed.), Biology of the laboratory mouse, 2nd ed. McGraw-Hill Book Company, New York, N.Y.
29. Stroupe, S. T., S. S. Craig, C. M. Gorbea, and J. S. Bond. 1991. Sex-related differences in meprin-A, a membrane-bound mouse kidney proteinase. Am. J. Physiol. 261:E354-E361.
30. Takeuchi, O., T. Kawai, H. Sanjo, N. G. Copeland, D. J. Gilbert, N. A. Jenkins, K. Takeda, and S. Akira. 1999. TLR6: a novel member of an expanding toll-like receptor family. Gene 231:59-65.[CrossRef][Medline]
31. Tang, W. W., L. Feng, Y. Xia, and C. B. Wilson. 1994. Extracellular matrix accumulation in immune-mediated tubulointerstitial injury. Kidney Int. 45:1077-1084.[Medline]
32. Trachtman, H., R. Greenwald, S. Moak, J. Tang, and J. S. Bond. 1993. Meprin activity in rats with experimental renal disease. Life Sci. 53:1339-1344.[CrossRef][Medline]
33. Trachtman, H., E. Valderrama, J. M. Dietrich, and J. S. Bond. 1995. The role of meprin A in the pathogenesis of acute renal failure. Biochem. Biophys. Res. Commun. 208:498-505.[CrossRef][Medline]
34. Uren, A. G., and D. L. Vaux. 1996. TRAF proteins and meprins share a conserved domain. Trends Biochem. Sci. 21:244-245.[CrossRef][Medline]
35. Walker, P. D., G. P. Kaushal, and S. V. Shah. 1998. Meprin A, the major matrix degrading enzyme in renal tubules, produces a novel nidogen fragment in vitro and in vivo. Kidney Int. 53:1673-1680.[CrossRef][Medline]
36. Zapata, J. M., K. Pawlowski, E. Haas, C. F. Ware, A. Godzik, and J. C. Reed. 2001. A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains. J. Biol. Chem. 276:24242-24252.
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| J. Bacteriol. | J. Virol. | Eukaryot. Cell |
|---|
| Microbiol. Mol. Biol. Rev. | Clin. Vaccine Immunol. | All ASM Journals |
|---|
