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It arises from donor-specific antibodies against HLA antigens, which induce maladaptive responses in the glomeruli and tubulointerstitium. An unbiased proteomics analysis of laser-captured\/microdissected glomeruli and tubulointerstitium from 30 indication kidney biopsy specimens with early AMR, acute cellular rejection, or acute tubular necrosis, quantified &gt;2000 proteins in each compartment. Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. Two ECM-modifying proteins, galectin-1 (LGALS1) and glutathione S-transferase\n                      <jats:italic toggle=\"yes\">\u03c9<\/jats:italic>\n                      -1 (GSTO1), were significantly increased in glomeruli and tubulointerstitium, respectively. Anti-HLA antibodies or AMR-related cytokines upregulated LGALS1 and GSTO1 in primary kidney cells, and may represent therapeutic targets to ameliorate ECM remodeling in AMR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Antibody-mediated rejection (AMR) accounts for &gt;50% of kidney allograft loss. Donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium cause AMR while inflammatory cytokines such as TNF\n                      <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                      trigger graft injury. The mechanisms governing cell-specific injury in AMR remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Unbiased proteomic analysis of laser-captured and microdissected glomeruli and tubulointerstitium was performed on 30 for-cause kidney biopsy specimens with early AMR, acute cellular rejection (ACR), or acute tubular necrosis (ATN).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 107 of 2026 glomerular and 112 of 2399 tubulointerstitial proteins was significantly differentially expressed in AMR versus ACR; 112 of 2026 glomerular and 181 of 2399 tubulointerstitial proteins were significantly dysregulated in AMR versus ATN (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. Glomerular and tubulointerstitial laminin subunit\n                      <jats:italic toggle=\"yes\">\u03b3<\/jats:italic>\n                      -1 (LAMC1) expression decreased in AMR, as did glomerular nephrin (NPHS1) and receptor-type tyrosine-phosphatase O (PTPRO). The proteomic analysis revealed upregulated galectin-1, which is an immunomodulatory protein linked to the ECM, in AMR glomeruli. Anti-HLA class I antibodies significantly increased cathepsin-V (CTSV) expression and galectin-1 expression and secretion in human glomerular endothelial cells. CTSV had been predicted to cleave ECM proteins in the AMR glomeruli. Glutathione S-transferase\n                      <jats:italic toggle=\"yes\">\u03c9<\/jats:italic>\n                      -1, an ECM-modifying enzyme, was significantly increased in the AMR tubulointerstitium and in TNF\n                      <jats:italic toggle=\"yes\">\u03b1<\/jats:italic>\n                      -treated proximal tubular epithelial cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Basement membranes are often remodeled in chronic AMR. Proteomic analysis performed on laser-captured and microdissected glomeruli and tubulointerstitium identified early ECM remodeling, which may represent a new therapeutic opportunity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2020030286","type":"journal-article","created":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T20:46:26Z","timestamp":1599597986000},"page":"2705-2724","source":"Crossref","is-referenced-by-count":46,"title":["Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study"],"prefix":"10.1681","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6965-4403","authenticated-orcid":false,"given":"Sergi","family":"Clotet-Freixas","sequence":"first","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3179-5542","authenticated-orcid":false,"given":"Caitriona M.","family":"McEvoy","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"},{"name":"Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ihor","family":"Batruch","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Pastrello","sequence":"additional","affiliation":[{"name":"Krembil Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Kotlyar","sequence":"additional","affiliation":[{"name":"Krembil Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2419-7736","authenticated-orcid":false,"given":"Julie Anh Dung","family":"Van","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"},{"name":"Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhurangi","family":"Arambewela","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Boshart","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"},{"name":"Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Farkona","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Niu","sequence":"additional","affiliation":[{"name":"Krembil Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhong","family":"Li","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olusegun","family":"Famure","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Bozovic","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vathany","family":"Kulasingam","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peixuen","family":"Chen","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Joseph","family":"Kim","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"},{"name":"Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Chan","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajad","family":"Moshkelgosha","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"},{"name":"Division of Respirology, Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Ashiqur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Center for Systems Immunology, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania"},{"name":"Center for Systems Immunology, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5747-064X","authenticated-orcid":false,"given":"Jishnu","family":"Das","sequence":"additional","affiliation":[{"name":"Center for Systems Immunology, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania"},{"name":"Center for Systems Immunology, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, 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Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan","family":"John","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6672-355X","authenticated-orcid":false,"given":"Ana","family":"Konvalinka","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada"},{"name":"Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada"},{"name":"Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"},{"name":"Soham and 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