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Clinical Research
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Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study

Sergi Clotet-Freixas, Caitriona M. McEvoy, Ihor Batruch, Chiara Pastrello, Max Kotlyar, Julie Anh Dung Van, Madhurangi Arambewela, Alex Boshart, Sofia Farkona, Yun Niu, Yanhong Li, Olusegun Famure, Andrea Bozovic, Vathany Kulasingam, Peixuen Chen, S. Joseph Kim, Emilie Chan, Sajad Moshkelgosha, Syed Ashiqur Rahman, Jishnu Das, Tereza Martinu, Stephen Juvet, Igor Jurisica, Andrzej Chruscinski, Rohan John and Ana Konvalinka
JASN November 2020, 31 (11) 2705-2724; DOI: https://doi.org/10.1681/ASN.2020030286
Sergi Clotet-Freixas
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
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Caitriona M. McEvoy
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
2Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
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Ihor Batruch
3Department of Laboratory Medicine and Pathobiology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
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Chiara Pastrello
4Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
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Max Kotlyar
4Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
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Julie Anh Dung Van
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
5Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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Madhurangi Arambewela
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
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Alex Boshart
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
5Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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Sofia Farkona
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
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Yun Niu
4Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
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Yanhong Li
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
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Olusegun Famure
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
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Andrea Bozovic
6Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
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Vathany Kulasingam
6Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
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Peixuen Chen
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
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S. Joseph Kim
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
2Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
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Emilie Chan
2Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
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Sajad Moshkelgosha
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
7Division of Respirology, Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
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Syed Ashiqur Rahman
8Center for Systems Immunology, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
9Center for Systems Immunology, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Jishnu Das
8Center for Systems Immunology, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
9Center for Systems Immunology, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Tereza Martinu
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
7Division of Respirology, Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
10Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, Ontario, Canada
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Stephen Juvet
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
7Division of Respirology, Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
10Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, Ontario, Canada
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Igor Jurisica
4Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
11Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
12Department of Computer Science, University of Toronto, Toronto, Ontario, Canada
13Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
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Andrzej Chruscinski
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
10Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, Ontario, Canada
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Rohan John
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
6Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
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Ana Konvalinka
1Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
2Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
5Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
6Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
10Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, Ontario, Canada
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Visual Abstract

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Significance Statement

Antibody-mediated rejection (AMR) accounts for more than 50% of kidney allograft loss. 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 >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 ω-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.

Abstract

Background Antibody-mediated rejection (AMR) accounts for >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 TNFα trigger graft injury. The mechanisms governing cell-specific injury in AMR remain unclear.

Methods 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).

Results 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 (P<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. Glomerular and tubulointerstitial laminin subunit γ-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 ω-1, an ECM-modifying enzyme, was significantly increased in the AMR tubulointerstitium and in TNFα-treated proximal tubular epithelial cells.

Conclusions 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.

  • acute allograft rejection
  • extracellular matrix
  • glomerular endothelial cells
  • proximal tubule
  • renal biopsy
  • kidney transplantation
  • Copyright © 2020 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 31 (11)
Journal of the American Society of Nephrology
Vol. 31, Issue 11
November 2020
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Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study
Sergi Clotet-Freixas, Caitriona M. McEvoy, Ihor Batruch, Chiara Pastrello, Max Kotlyar, Julie Anh Dung Van, Madhurangi Arambewela, Alex Boshart, Sofia Farkona, Yun Niu, Yanhong Li, Olusegun Famure, Andrea Bozovic, Vathany Kulasingam, Peixuen Chen, S. Joseph Kim, Emilie Chan, Sajad Moshkelgosha, Syed Ashiqur Rahman, Jishnu Das, Tereza Martinu, Stephen Juvet, Igor Jurisica, Andrzej Chruscinski, Rohan John, Ana Konvalinka
JASN Nov 2020, 31 (11) 2705-2724; DOI: 10.1681/ASN.2020030286

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Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study
Sergi Clotet-Freixas, Caitriona M. McEvoy, Ihor Batruch, Chiara Pastrello, Max Kotlyar, Julie Anh Dung Van, Madhurangi Arambewela, Alex Boshart, Sofia Farkona, Yun Niu, Yanhong Li, Olusegun Famure, Andrea Bozovic, Vathany Kulasingam, Peixuen Chen, S. Joseph Kim, Emilie Chan, Sajad Moshkelgosha, Syed Ashiqur Rahman, Jishnu Das, Tereza Martinu, Stephen Juvet, Igor Jurisica, Andrzej Chruscinski, Rohan John, Ana Konvalinka
JASN Nov 2020, 31 (11) 2705-2724; DOI: 10.1681/ASN.2020030286
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Keywords

  • acute allograft rejection
  • extracellular matrix
  • glomerular endothelial cells
  • proximal tubule
  • renal biopsy
  • kidney transplantation

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