PXD022074

PXD022074 is an original dataset announced via ProteomeXchange.

Title	Brain death associated activation of Calpain-Talin axis in donor kidneys underlies podocyte matrix degradation and graft dysfunction in kidney transplantation
Description	Deceased kidney donation after brain death (DBD) is the main source of transplants, yet these grafts yield inferior transplant outcomes when compared to living donation. In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that proteolytic processes in DBD kidneys might lead to podocyte damage with subsequent development of post-transplant dysfunction. Using protein topography and migration analysis platform (PROTOMAP), we mapped degradation profiles of cytoskeletal proteins in DBD kidneys. Cytoskeletal proteolytic degradation was further studied by Immunoblotting on a separate cohort of deceased and living donor kidney biopsies. To investigate potential mechanism of kidney cytoskeletal protein degradation, in-vitro human podocytes and ex-vivo precision-cut human kidney slices were employed. We found novel proteolytic profiles of key podocyte cytoskeletal proteins in donor kidneys associated with suboptimal posttransplant function. These were unique to brain-death and were not observed in circulatory-death or living-donor kidneys. Talin-specific protein degradation in DBD kidneys indicated Calpain-1 activation may have a key role in proteolytic processes observed in the dysfunctional kidneys. Investigation of the underlying mechanism suggests that Transforming-Growth Factor-β (TGFβ) induces Calpain-1 activation, leading to brain-death specific podocyte degradation patterns and dysregulation of actin cytoskeleton; events that were prevented, in-vitro, by Calpain inhibition. Conclusion Our data demonstrate that podocyte protein degradation impacts the quality of DBD kidneys, propose a role of TGFβ mediated Calpain-1 proteolytic processing of cytoskeletal Talin-1, suggesting therapeutic opportunities to prevent kidney dysfunction.
HostingRepository	PRIDE
AnnounceDate	2022-08-12
AnnouncementXML	Submission_2022-08-11_19:58:15.889.xml
DigitalObjectIdentifier	http://dx.doi.org/10.6019/PXD022074
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Philip Charles
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-10-19 05:18:37	ID requested
⏵ 1	2022-08-11 19:58:16	announced

Vaughan RH, Kresse JC, Farmer LK, Th, é, z, é, nas ML, Kessler BM, Lindeman JHN, Sharples EJ, Welsh GI, N, ø, rregaard R, Ploeg RJ, Kaisar M, Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes. Am J Transplant, 22(4):1073-1087(2022) [pubmed]

submitter keyword: Kidney transplantation, podocytes, allograft dysfunction, donation after brain death (DBD), protein degradation, kidney cytoskeleton

Maria Kaisar
contact affiliation	Research and Development, NHS Blood and Transplant Nuffield Department of Surgical Sciences, and Oxford Biomedical Research Centre, University of Oxford
contact email	maria.kaisar@nds.ox.ac.uk
lab head
Philip Charles
contact affiliation	University of Oxford
contact email	philip.charles@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD022074
     1. Label: PRIDE project
     2. Name: Brain death associated activation of Calpain-Talin axis in donor kidneys underlies podocyte matrix degradation and graft dysfunction in kidney transplantation