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PXD022074 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleBrain death associated activation of Calpain-Talin axis in donor kidneys underlies podocyte matrix degradation and graft dysfunction in kidney transplantation
DescriptionDeceased 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.
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterPhilip Charles
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-10-19 05:18:37ID requested
12022-08-11 19:58:16announced
Publication List
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]
Keyword List
submitter keyword: Kidney transplantation, podocytes, allograft dysfunction, donation after brain death (DBD), protein degradation, kidney cytoskeleton
Contact List
Maria Kaisar
contact affiliationResearch and Development, NHS Blood and Transplant Nuffield Department of Surgical Sciences, and Oxford Biomedical Research Centre, University of Oxford
contact emailmaria.kaisar@nds.ox.ac.uk
lab head
Philip Charles
contact affiliationUniversity of Oxford
contact emailphilip.charles@ndm.ox.ac.uk
dataset submitter
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