Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study Journal Articles uri icon

  • Overview
  • Research
  • Identity
  • Additional Document Info
  • View All


  • 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. 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.


  • Clotet-Freixas, Sergi
  • McEvoy, Caitriona M
  • Batruch, Ihor
  • Pastrello, Chiara
  • Kotlyar, Max
  • Van, Julie Anh Dung
  • Arambewela, Madhurangi
  • Boshart, Alex
  • Farkona, Sofia
  • Niu, Yun
  • Li, Yanhong
  • Famure, Olusegun
  • Bozovic, Andrea
  • Kulasingam, Vathany
  • Chen, Peixuen
  • Kim, S Joseph
  • Chan, Emilie
  • Moshkelgosha, Sajad
  • Rahman, Syed Ashiqur
  • Das, Jishnu
  • Martinu, Tereza
  • Juvet, Stephen
  • Jurisica, Igor
  • Chruscinski, Andrzej
  • John, Rohan
  • Konvalinka, Ana

publication date

  • November 2020

has subject area