The Role of Galectin-1 and Basement Membrane Remodeling in Kidney Antibody-Mediated Rejection

S. Clotet-Freixas¹, C. McEvoy¹, I. Batruch², M. Kotlyar³, C. Pastrello³, J. Van¹, M. Arambewela¹, A. Boshart¹, S. Farkona¹, A. Bozovic⁴, V. Kulasingam⁴, P. Chen¹, I. Jurisica³, A. Chruscinski¹, R. John⁴, A. Konvalinka⁵

¹Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada, ²Department of Laboratory Medicine and Pathobiology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada, ³Krembil Research Institute, University Health Network, Toronto, ON, Canada, ⁴Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, ⁵Department of Medicine, Division of Nephrology, University Health Network, Toronto, ON, Canada

Meeting: 2020 American Transplant Congress

Abstract number: A-351

Keywords: Antigen presentation, Endothelial cells, HLA antibodies, Kidney transplantation

Session Information

Session Name: Poster Session A: Acute Rejection

Session Type: Poster Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:00pm

Presentation Time: 3:30pm-4:00pm

Location: Virtual

*Purpose: Antibody-mediated rejection (AMR), the leading cause of kidney graft loss, is caused by anti-HLA and non-HLA antibodies against proteins in two main kidney compartments: glomeruli and tubulointerstitium (TI). We hypothesized that acute AMR is associated with compartment-specific proteome alterations that may uncover mechanisms of early antibody-mediated injury.

*Methods: We performed laser capture-microdissection of glomeruli and TI from indication kidney graft biopsies of 7 pure AMR cases and 23 matched ‘non-AMR’ cases with acute cellular rejection (ACR) or acute tubular necrosis (ATN). Glomeruli and TI were subjected to unbiased proteomics analyses. Human primary glomerular microvascular endothelial cells (HGMEC) were used for in vitro validation.

*Results: The median post-transplant graft age at the time of the biopsy was 11 days. AMR biopsies were C4d+ and no biopsies had chronic lesions. We identified 2026 proteins in glomeruli and 2399 in TI. 120 glomerular proteins and 180 TI proteins were differentially expressed in AMR vs. non-AMR (p<0.05). Proteins involved in HLA presentation were increased in AMR. Proteins decreased in both AMR compartments (e.g. LAMC1, NID1) were components of the basement membranes (BM). Decreased levels of LAMC1 in both AMR compartments were validated by immunostaining. Cathepsin V (CTSV) was predicted to cleave glomerular BM proteins decreased in AMR. Protein-protein interaction network analysis of proteins increased in the AMR glomeruli identified galectin-1 (LGALS1) as a central node. LGALS1 is a key immunomodulatory protein linked to BM remodeling. In vitro, anti-HLA class I antibody significantly increased CTSV and LGALS1 gene expression, and LGALS1 secretion in HGMEC.

*Conclusions: BMs are often remodeled in chronic AMR. Thus, our proteomic findings may point to previously unrecognized, early BM alterations in AMR. LGALS1 and early BM remodeling may represent new therapeutic opportunities in AMR.

To cite this abstract in AMA style:

Clotet-Freixas S, McEvoy C, Batruch I, Kotlyar M, Pastrello C, Van J, Arambewela M, Boshart A, Farkona S, Bozovic A, Kulasingam V, Chen P, Jurisica I, Chruscinski A, John R, Konvalinka A. The Role of Galectin-1 and Basement Membrane Remodeling in Kidney Antibody-Mediated Rejection [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/the-role-of-galectin-1-and-basement-membrane-remodeling-in-kidney-antibody-mediated-rejection/. Accessed November 22, 2024.

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