1. Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study.
- Author
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Clotet-Freixas S, McEvoy CM, Batruch I, Pastrello C, Kotlyar M, Van JAD, Arambewela M, Boshart A, Farkona S, Niu Y, Li Y, Famure O, Bozovic A, Kulasingam V, Chen P, Kim SJ, Chan E, Moshkelgosha S, Rahman SA, Das J, Martinu T, Juvet S, Jurisica I, Chruscinski A, John R, and Konvalinka A
- Subjects
- Adult, Aged, Allografts metabolism, Allografts pathology, Antibodies metabolism, Biopsy, Cathepsins metabolism, Cell Line, Cysteine Endopeptidases metabolism, Extracellular Matrix pathology, Female, Galectin 1 genetics, Galectin 1 metabolism, Gene Expression, Glutathione Transferase metabolism, Graft Rejection genetics, Histocompatibility Antigens Class I immunology, Humans, Kidney Glomerulus metabolism, Kidney Transplantation, Kidney Tubules metabolism, Laminin metabolism, Male, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 3 metabolism, Membrane Proteins metabolism, Middle Aged, Necrosis, Proteomics, Receptor-Like Protein Tyrosine Phosphatases, Class 3 metabolism, Tumor Necrosis Factor-alpha pharmacology, Basement Membrane metabolism, Extracellular Matrix metabolism, Graft Rejection metabolism, Graft Rejection pathology, Kidney Glomerulus pathology, Kidney Tubules pathology
- 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 TNF α 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 TNF α -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., (Copyright © 2020 by the American Society of Nephrology.)
- Published
- 2020
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