PXD017580

PXD017580 is an original dataset announced via ProteomeXchange.

Title	Proteomics Reveals Extracellular Matrix Injury in the Glomeruli and Tubulointerstitium of Kidney Allografts with Early Antibody-Mediated Rejection
Description	Antibody-mediated rejection (AMR) accounts for >50% of kidney allograft losses. AMR is caused by donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium, which together with high interferon gamma (IFNɣ) and tumor necrosis factor-alpha (TNFα), trigger graft injury. Unfortunately, the mechanisms governing cell-specific injury in AMR remain unclear. We studied 30 for-cause kidney biopsies with early AMR, acute cellular rejection or acute tubular necrosis (‘non-AMR’). We laser-captured microdissected glomeruli and tubulointerstitium and subjected them to unbiased proteome analysis. 120/2026 glomerular and 180/2399 tubulointerstitial proteins were significantly differentially expressed in AMR vs. non-AMR biopsies (p<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. We verified decreased glomerular and tubulointerstitial LAMC1 expression, and decreased glomerular NPHS1 and PTPRO expression in AMR. Cathepsin-V (CTSV) was predicted to cleave ECM-proteins in the AMR glomeruli, and CTSL, CTSS and LGMN in the tubulointerstitium. We identified galectin-1, an immunomodulatory protein upregulated in AMR glomeruli and linked to the ECM. Anti-HLA class-I antibodies significantly increased CTSV expression, and galectin-1 expression and secretion, in human glomerular endothelial cells. We also studied glutathione S-transferase omega-1 (GSTO1), an ECM-modifying enzyme, increased in the AMR tubulointerstitium. GSTO1 expression was significantly increased in TNFα-treated proximal tubular epithelial cells. IFNɣ and TNFα significantly increased CTSS and LGMN expression in these cells. Basement membranes are often remodeled in chronic AMR, and we demonstrated that this remodeling begins early in glomeruli and tubulointerstitium. Targeting ECM-remodeling in AMR may represent a new therapeutic opportunity.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:12:36.049.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sergi Clotet Freixas
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-02-18 02:44:17	ID requested
1	2020-09-22 06:08:34	announced
⏵ 2	2024-10-22 05:12:44	announced	2024-10-22: Updated project metadata.

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, Konvalinka A, Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study. J Am Soc Nephrol, 31(11):2705-2724(2020) [pubmed]

10.1681/asn.2020030286;

submitter keyword: Glomeruli, Basement membrane, Glomerular microvascular endothelial cells, Tubulointerstitium, Systems Biology, HLA class-I, Antibody-mediated rejection, Biopsy,Kidney, Cathepsins., Laser-capture microdissection, Proximal tubular epithelial cells, Laminin, Galectin-1, Glutathione S-transferase omega-1, Extracellular matrix, Cytokines, Remodeling, Proteomics

Ana Konvalinka
contact affiliation	Toronto General Hospital Research Institute, UniversityHealth Network, Toronto, Canada Department of Medicine, Division of Nephrology, University Health Network, Toronto, Canada
contact email	Ana.Konvalinka@uhn.ca
lab head
Sergi Clotet Freixas
contact affiliation	University Health Network
contact email	sergi.clotetfreixas@uhnresearch.ca
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/09/PXD017580

PRIDE project URI

• PRIDE
  1. PXD017580
     1. Label: PRIDE project
     2. Name: Proteomics Reveals Extracellular Matrix Injury in the Glomeruli and Tubulointerstitium of Kidney Allografts with Early Antibody-Mediated Rejection