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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Deletion of <italic>Cd151</italic> Results in a Strain-Dependent Glomerular Disease Due to Severe Alterations of the Glomerular Basement Membrane</title><author><name sortKey="Baleato, Rosa M" sort="Baleato, Rosa M" uniqKey="Baleato R" first="Rosa M." last="Baleato">Rosa M. Baleato</name><affiliation><nlm:aff id="N0x351f510N0x40f7bd8"></nlm:aff></affiliation></author><author><name sortKey="Guthrie, Petrina L" sort="Guthrie, Petrina L" uniqKey="Guthrie P" first="Petrina L." last="Guthrie">Petrina L. Guthrie</name><affiliation><nlm:aff id="N0x351f510N0x40f7bd8"></nlm:aff></affiliation></author><author><name sortKey="Gubler, Marie Claire" sort="Gubler, Marie Claire" uniqKey="Gubler M" first="Marie-Claire" last="Gubler">Marie-Claire Gubler</name><affiliation><nlm:aff id="N0x351f510N0x40f7bd8"></nlm:aff></affiliation></author><author><name sortKey="Ashman, Leonie K" sort="Ashman, Leonie K" uniqKey="Ashman L" first="Leonie K." last="Ashman">Leonie K. Ashman</name><affiliation><nlm:aff id="N0x351f510N0x40f7bd8"></nlm:aff></affiliation></author><author><name sortKey="Roselli, Severine" sort="Roselli, Severine" uniqKey="Roselli S" first="Séverine" last="Roselli">Séverine Roselli</name><affiliation><nlm:aff id="N0x351f510N0x40f7bd8"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">18787104</idno><idno type="pmc">2543062</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2543062</idno><idno type="RBID">PMC:2543062</idno><idno type="doi">10.2353/ajpath.2008.071149</idno><date when="2008">2008</date><idno type="wicri:Area/Pmc/Corpus">000989</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000989</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Deletion of <italic>Cd151</italic> Results in a Strain-Dependent Glomerular Disease Due to Severe Alterations of the Glomerular Basement Membrane</title><author><name sortKey="Baleato, Rosa M" sort="Baleato, Rosa M" uniqKey="Baleato R" first="Rosa M." last="Baleato">Rosa M. Baleato</name><affiliation><nlm:aff id="N0x351f510N0x40f7bd8"></nlm:aff></affiliation></author><author><name sortKey="Guthrie, Petrina L" sort="Guthrie, Petrina L" uniqKey="Guthrie P" first="Petrina L." last="Guthrie">Petrina L. Guthrie</name><affiliation><nlm:aff id="N0x351f510N0x40f7bd8"></nlm:aff></affiliation></author><author><name sortKey="Gubler, Marie Claire" sort="Gubler, Marie Claire" uniqKey="Gubler M" first="Marie-Claire" last="Gubler">Marie-Claire Gubler</name><affiliation><nlm:aff id="N0x351f510N0x40f7bd8"></nlm:aff></affiliation></author><author><name sortKey="Ashman, Leonie K" sort="Ashman, Leonie K" uniqKey="Ashman L" first="Leonie K." last="Ashman">Leonie K. Ashman</name><affiliation><nlm:aff id="N0x351f510N0x40f7bd8"></nlm:aff></affiliation></author><author><name sortKey="Roselli, Severine" sort="Roselli, Severine" uniqKey="Roselli S" first="Séverine" last="Roselli">Séverine Roselli</name><affiliation><nlm:aff id="N0x351f510N0x40f7bd8"></nlm:aff></affiliation></author></analytic><series><title level="j">The American Journal of Pathology</title><idno type="ISSN">0002-9440</idno><idno type="eISSN">1525-2191</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Alterations in CD151 have been associated with primary glomerular disease in both humans and mice, implicating CD151 as a key component of the glomerular filtration barrier. CD151 belongs to the tetraspanin family and associates with cell-matrix adhesion complexes such as α3β1-integrin. Here we show that <bold><italic>Cd151</italic></bold>-deficient mice develop severe kidney disease on an FVB background but are healthy on a B6 background, providing a new and unique tool for the identification of genes that modulate the onset of proteinuria. To better understand the function of CD151 in the kidney, we studied its expression pattern and characterized early ultrastructural defects in <bold><italic>Cd151</italic></bold>-null kidneys. CD151 is expressed in podocytes of the mouse kidney and co-localizes with α3-integrin at the base of podocyte foot processes, at the site of anchorage to the glomerular basement membrane (GBM). Interestingly, the first ultrastructural lesions seen at the onset of proteinuria in <bold><italic>Cd151</italic></bold>-null kidneys were severe alterations of the GBM, reminiscent of Alport syndrome and consisting of massive thickening and splitting of the GBM. These lesions are associated with increased expression of GBM components. Podocyte abnormalities, effacement of foot processes, and podocyte loss appear to occur consequently to the GBM damage. In conclusion, CD151 appears to be involved in the establishment, maturation, and/or maintenance of the GBM structure in addition to its role in integrin-mediated adhesion strengthening.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Pathol</journal-id><journal-title>The American Journal of Pathology</journal-title><issn pub-type="ppub">0002-9440</issn><issn pub-type="epub">1525-2191</issn><publisher><publisher-name>American Society for Investigative Pathology</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18787104</article-id><article-id pub-id-type="pmc">2543062</article-id><article-id pub-id-type="doi">10.2353/ajpath.2008.071149</article-id><article-categories><subj-group subj-group-type="heading"><subject>Regular Articles</subject><subj-group><subject>Cardiovascular, Pulmonary and Renal Pathology</subject></subj-group></subj-group></article-categories><title-group><article-title>Deletion of <italic>Cd151</italic> Results in a Strain-Dependent Glomerular Disease Due to Severe Alterations of the Glomerular Basement Membrane</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Baleato</surname><given-names>Rosa M.</given-names></name><xref ref-type="aff" rid="N0x351f510N0x40f7bd8">*</xref></contrib><contrib contrib-type="author"><name><surname>Guthrie</surname><given-names>Petrina L.</given-names></name><xref ref-type="aff" rid="N0x351f510N0x40f7bd8">*</xref></contrib><contrib contrib-type="author"><name><surname>Gubler</surname><given-names>Marie-Claire</given-names></name><xref ref-type="aff" rid="N0x351f510N0x40f7bd8">†</xref></contrib><contrib contrib-type="author"><name><surname>Ashman</surname><given-names>Leonie K.</given-names></name><xref ref-type="aff" rid="N0x351f510N0x40f7bd8">*</xref></contrib><contrib contrib-type="author"><name><surname>Roselli</surname><given-names>Séverine</given-names></name><xref ref-type="aff" rid="N0x351f510N0x40f7bd8">*</xref></contrib><aff id="N0x351f510N0x40f7bd8">From the School of Biomedical Sciences and Hunter Medical Research Institute,<label>*</label> University of Newcastle, Newcastle, NSW, Australia; INSERM U574,<label>†</label> Hôpital Necker-Enfants Malades, Paris, France</aff></contrib-group><pub-date pub-type="ppub"><month>10</month><year>2008</year></pub-date><volume>173</volume><issue>4</issue><fpage>927</fpage><lpage>937</lpage><history><date date-type="accepted"><day>24</day><month>6</month><year>2008</year></date></history><permissions><copyright-statement>Copyright © American Society for Investigative Pathology</copyright-statement><copyright-year>2008</copyright-year></permissions><self-uri xlink:title="pdf" xlink:href="zjh01008000927.pdf"></self-uri><abstract><p>Alterations in CD151 have been associated with primary glomerular disease in both humans and mice, implicating CD151 as a key component of the glomerular filtration barrier. CD151 belongs to the tetraspanin family and associates with cell-matrix adhesion complexes such as α3β1-integrin. Here we show that <bold><italic>Cd151</italic></bold>-deficient mice develop severe kidney disease on an FVB background but are healthy on a B6 background, providing a new and unique tool for the identification of genes that modulate the onset of proteinuria. To better understand the function of CD151 in the kidney, we studied its expression pattern and characterized early ultrastructural defects in <bold><italic>Cd151</italic></bold>-null kidneys. CD151 is expressed in podocytes of the mouse kidney and co-localizes with α3-integrin at the base of podocyte foot processes, at the site of anchorage to the glomerular basement membrane (GBM). Interestingly, the first ultrastructural lesions seen at the onset of proteinuria in <bold><italic>Cd151</italic></bold>-null kidneys were severe alterations of the GBM, reminiscent of Alport syndrome and consisting of massive thickening and splitting of the GBM. These lesions are associated with increased expression of GBM components. Podocyte abnormalities, effacement of foot processes, and podocyte loss appear to occur consequently to the GBM damage. In conclusion, CD151 appears to be involved in the establishment, maturation, and/or maintenance of the GBM structure in addition to its role in integrin-mediated adhesion strengthening.</p></abstract></article-meta></front><floats-wrap><fig position="float" id="F1-7732"><label>Figure 1</label><caption><p>Massive Proteinuria in <italic>Cd151</italic>-Null Mice on the FVB but Not B6 Background. Urine from <italic>Cd151</italic><sup>+/+</sup> and <italic>Cd151</italic><sup>−/−</sup> mice at different ages was analyzed by SDS- polyacrylamide gel electrophoresis. One microliter of urine from each mouse was loaded on the same gel. Proteinuria was observed as early as 5 days of age in the FVB <italic>Cd151</italic>-null mouse and increased substantially with age to become massive at 12 weeks (note that the urine sample of the 12 week-old FVB <italic>Cd151</italic>-null mouse has been diluted 1:10). B6 <italic>Cd151</italic>-null mice were analyzed up to 12 months of age and did not exhibit any signs of proteinuria.</p></caption><graphic xlink:href="zjh0100877320001"></graphic></fig><fig position="float" id="F2-7732"><label>Figure 2</label><caption><p>Histological Analysis of <italic>Cd151</italic><sup>−/−</sup> Kidneys. <italic>Cd151</italic><sup>+/+</sup> and <italic>Cd151</italic><sup>−/−</sup> Kidneys from both FVB (<bold>A–F</bold>; <bold>I–L</bold>) and B6 strains (<bold>G, H, M, N</bold>) were analyzed by H&E (<bold>A–H</bold>) and PAS staining (<bold>I–N</bold>). At 4 weeks of age, FVB <italic>Cd151</italic>-null mice presented with mild glomerular damage as seen by H&E staining (black <bold>arrow head</bold> in <bold>B</bold>) compared to wild-type (<bold>A</bold>). At this age, the glomerular damage consisted exclusively of GBM thickening as seen on the PAS stains (<bold>I, J</bold>). By 12 week of age, all FVB <italic>Cd151</italic>-null mice showed significantly increased kidney damage (<bold>D–F</bold>) compared to wild-type control (<bold>C</bold>), ranging from moderate glomerular damage (<bold>D</bold>, black <bold>arrow</bold>) to more severe glomerular damage associated with tubular lesions (<bold>E</bold>). The GBM of <italic>Cd151</italic><sup>−/−</sup> mice at this age was extensively thickened (<bold>L</bold>). In addition, a few 12-week-old FVB <italic>Cd151</italic>-null mice presented with massive glomerulosclerosis and collapse of the glomerular tuft (<bold>E, F,</bold> white <bold>arrowhead</bold>) associated with massive tubular dilations and protein casts (<bold>E</bold>*). Some sclerotic glomeruli showed partial (<bold>F</bold>, black <bold>arrowhead</bold>) or complete (<bold>F</bold>, white <bold>arrowhead</bold>) adhesion to the Bowman’s capsule. The 12 month-old B6 <italic>Cd151</italic>-null kidneys appeared totally normal (<bold>H, N</bold>) as compared with wild-type controls (<bold>G, M</bold>). Scale bars = 50 μm.</p></caption><graphic xlink:href="zjh0100877320002"></graphic></fig><fig position="float" id="F3-7732"><label>Figure 3</label><caption><p>Localization of CD151 in the Mouse Kidney. Dual immunofluorescence labeling and confocal analysis using CD151 antibody (green) and antibodies (red) directed against nidogen (<bold>A–C</bold>), podocin (<bold>D–F</bold>), α3 integrin (<bold>G–I</bold>), and CD31 (<bold>J–L</bold>). The CD151 antibody labeled mainly glomeruli in the kidney (<bold>A–O</bold>). The specificity of the CD151 antibody was shown by absence of CD151 labeling on <italic>Cd151</italic><sup>−/−</sup> section (<bold>P–R</bold>). The green CD151 labeling follows the GBM (red, <bold>C</bold>) and colocalizes substantially with podocin (<bold>F</bold>) and α3 integrin (<bold>I</bold>) at the base of podocytes. CD151 does not colocalize with CD31 in the glomerular endothelium (<bold>L</bold>). <bold>M–O:</bold> For labeling where two rabbit antibodies were used, an appropriate control (where the second primary antibody was omitted) was included in the experiments (<bold>M–O</bold>). The absence of labeling by the second secondary antibody (red) in this control proves sufficient blocking of the first primary (CD151) and secondary antibody (green). Pictures were taken using a confocal microscope. Original magnification ×400.</p></caption><graphic xlink:href="zjh0100877320003"></graphic></fig><fig position="float" id="F4-7732"><label>Figure 4</label><caption><p>TEM study of FVB <italic>Cd151</italic><sup>−/−</sup> Kidneys. Five-day-old (<bold>A–D</bold>) and 3-week-old (<bold>E–H</bold>) FVB kidneys were analyzed by TEM. The GBM is abnormally and irregularly thickened in the 5-day- and 3-week-old FVB <italic>Cd151</italic>-null animals (*in <bold>B, C, F,</bold> and <bold>G</bold>). Normal differentiation and architecture of the glomerular filtration barrier in FVB wild-type animals is shown at 5 days (<bold>A</bold>) and 3 weeks (<bold>E</bold>) of age. GBM maturation is not yet complete in the 5-day-old wild-type FVB mice (box in <bold>A</bold>, <bold>white arrowhead</bold>). The striking feature in <italic>Cd151</italic>-null kidneys is the massive thickening and splitting of the GBM observed as early as 5 days in some segments of glomeruli (<bold>B, C</bold>*). The GBM disorganization becomes more important and involves more capillary loops with progression of the disease as shown here at 3 weeks of age (<bold>F, G</bold>*). Foot processes and slit diaphragms seem to develop normally as observed in the 5-day-old (<bold>C, D, arrows</bold>) and 3-week-old (<bold>H, arrow</bold>) <italic>Cd151</italic><sup>−/−</sup> animals (<bold>C, D arrows</bold>). The foot processes were effaced in a few areas (<bold>arrowhead</bold> in <bold>B</bold> and <bold>G</bold>) but they were surprisingly well maintained in other areas, given the extent of GBM damage (<bold>C, D,</bold> and <bold>H</bold>). A semiquantitative analysis of the extent of GBM splitting (<bold>I</bold>) and effacement of foot processes (<bold>J</bold>) over time was performed. The results are expressed as percentage of split GBM and number of podocyte foot processes (FP) per micrometer of GBM, respectively. The representative results from two mice in each group at 5 days and 3 weeks are shown. Scale bars = 2 μm (<bold>A, B, E, F</bold>); 500 nm <bold>C, D, G, H</bold>.</p></caption><graphic xlink:href="zjh0100877320004"></graphic></fig><fig position="float" id="F5-7732"><label>Figure 5</label><caption><p>SEM Analysis of Podocyte Structure in FVB <italic>Cd151</italic>-Null Mice. Three-and 12-week old FVB <italic>Cd151</italic><sup>+/+</sup> and <italic>Cd151</italic><sup>−/−</sup> kidneys were analyzed by SEM to determine the extent of glomerular and more specifically podocyte damage. In wild-type animals (<bold>A, B,</bold> and <bold>E</bold>) the podocyte structure is well defined with the cell body dividing into primary processes (PP) that divide into foot processes (FP). At 3 weeks of age, the podocytes look abnormal in <italic>Cd151</italic><sup>−/−</sup> kidneys (<bold>C, D</bold>) compared to wild-type controls (<bold>A, B</bold>). Indeed, the podocyte cell bodies look flattened at 3 weeks of age (<bold>C</bold>). Primary processes and foot processes are still present in most areas as seen by TEM but appear disorganized (<bold>C, D,</bold> and <bold>G</bold>). Podocyte alterations progress with age and foot process effacement has become more pronounced by 12 weeks (<bold>F</bold>). However, even at 12 weeks of age, there are still a number of places where disorganized foot processes are still visible (<bold>G</bold>). Also note the unhealthy podocyte sending a process onto the cell body of its neighbor (<bold>arrow</bold> in <bold>H</bold>). The representative results from 3 mice in each group at 3 weeks of age and two mice in each group at 12 weeks of age are shown. Three to 6 glomeruli were analyzed for each mouse. Original magnification: ×6000 (<bold>A, C</bold>); ×20,000 (<bold>B, D–G</bold>); ×12,000 (<bold>H</bold>).</p></caption><graphic xlink:href="zjh0100877320005"></graphic></fig><fig position="float" id="F6-7732"><label>Figure 6</label><caption><p>Progressive Podocyte Loss in FVB <italic>Cd151</italic><sup>−/−</sup> Kidneys. <bold>A:</bold> Podocyte number per glomerulus was estimated by counting nuclei positive for both WT1 and DAPI stainings. Results were normalized to the average podocyte number in the wild-type control for each age. At 5 days of age podocyte number in <italic>Cd151</italic><sup>−/−</sup> kidneys was equal to control, showing that the podocytes differentiate normally. At 3 weeks and 12 weeks of age FVB <italic>Cd151</italic>-deficient mice present with a significant decrease in podocyte number per glomerulus (22.2% and 28.4%, respectively), compared to wild-type controls (<italic>P</italic> < 0.001). In B6 <italic>Cd151</italic>-null animals there is no loss in podocyte number compared to wild-type controls. <bold>B:</bold> Representative pictures of the WT1 immunolabeling used to assess the number of podocytes per glomerulus in both wild-type (wt) and <italic>Cd151</italic> knock-out (ko) kidney sections. <bold>C:</bold> Representative Western blot of urine from <italic>Cd151</italic><sup>+/+</sup> and <italic>Cd151</italic><sup>−/−</sup> mice probed with WT1 antibody (<bold>top panel</bold>), showing presence of podocytes in urine of some <italic>Cd151</italic><sup>−/−</sup> mice at 3 weeks and 12 weeks of age (<bold>black arrow</bold>). Ponceau staining of the same membrane shows the extent of proteinuria for each mouse (<bold>bottom panel</bold>).</p></caption><graphic xlink:href="zjh0100877320006"></graphic></fig><fig position="float" id="F7-7732"><label>Figure 7</label><caption><p>Expression of Glomerular Basement Membrane Components in <italic>Cd151</italic>-Null Kidneys. Immunofluorescence analysis of GBM laminin chains (<bold>A–H</bold>), nidogen (<bold>I, J</bold>), and collagen type IV α1–5 chains (<bold>K–T</bold>) in 3-week old <italic>Cd151</italic><sup>+/+</sup> and <italic>Cd151</italic><sup>−/−</sup> kidneys. In wild-type kidneys at this age, the laminin network is composed of the α5, β2, and γ1 laminin chains (ie, laminin 521) (<bold>A, E, G</bold>) while the β1 chain of laminin has switched off in the GBM and is restricted to the mesangial matrix (<bold>C</bold>). In the <italic>Cd151</italic> knock-out kidneys however there is persistence of the laminin β1 chain in the GBM (<bold>D</bold>) together with expression of α5, β2, and γ1 laminin chains. All four chains of laminin also show increased expression specifically in the GBM, as does nidogen/entactin (<bold>I–J</bold>). In both 3-week-old wild-type and <italic>Cd151</italic><sup>−/−</sup> kidneys, the switch from the α1α1α2 collagen network to the α3α4α5 network has normally occurred (<bold>K–T</bold>). However there is a strong increase in expression of the α4 and α5 chains of collagen type IV in the thickened GBM of <italic>Cd151</italic><sup>−/−</sup> kidneys (<bold>R, T</bold>). The representative results from two mice in each group are shown. Original magnification: ×400.</p></caption><graphic xlink:href="zjh0100877320007"></graphic></fig></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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