In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 31, No. 11 ( 2020-11), p. 2705-2724
Abstract:
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 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.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2020030286
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2020
detail.hit.zdb_id:
2029124-3
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