Dataset Information

Brain death associated activation of Calpain-Talin axis in donor kidneys underlies podocyte matrix degradation and graft dysfunction in kidney transplantation

ABSTRACT: 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-Î² (TGFÎ²) 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 TGFÎ² mediated Calpain-1 proteolytic processing of cytoskeletal Talin-1, suggesting therapeutic opportunities to prevent kidney dysfunction.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Glomerular Visceral Epithelial Cell, Kidney

SUBMITTER: Philip Charles

LAB HEAD: Maria Kaisar

PROVIDER: PXD022074 | Pride | 2022-08-12

REPOSITORIES: Pride

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Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes.

Vaughan Rebecca H RH Kresse Jean-Claude JC Farmer Louise K LK Thézénas Marie L ML Kessler Benedikt M BM Lindeman Jan H N JHN Sharples Edward J EJ Welsh Gavin I GI Nørregaard Rikke R Ploeg Rutger J RJ Kaisar Maria M

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20220204 4

In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys adversely impacting the quality of grafts. Here, we hypothesized that donation after brain death (DBD) kidneys undergo proteolytic processes that may deem grafts susceptible to posttransplant dysfunction. Using mass spectrometry and immunoblotting, we mapped degradation profiles of cytoskeletal proteins in deceased and living donor kidney biopsies. We found that ...[more]

PMID: 34878723

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Dataset Information

Brain death associated activation of Calpain-Talin axis in donor kidneys underlies podocyte matrix degradation and graft dysfunction in kidney transplantation

Publications

Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes.

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