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

Rebecca Vaughan, Jean-Claude Kresse, Louise K Farmer, Marie Thézénas, Benedikt Kessler, Jan Lindeman, Edward Sharples, Gavin I Welsh, Rikke Nørregaard, Rutger Ploeg, Maria Kaisar*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

4 Citations (Scopus)
22 Downloads (Pure)

Abstract

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 DBD kidneys undergo proteolytic processes that may deem grafts susceptible to post-transplant dysfunction.
Using mass spectrometry and immunoblotting, we mapped degradation profiles of cytoskeletal proteins in deceased and living donor kidney biopsies. We found that key cytoskeletal proteins in DBD kidneys were proteolytically cleaved, generating peptide fragments, predominantly in grafts with suboptimal posttransplant function. Interestingly, α-actinin-4 and Talin-1 proteolytic fragments were detected in brain-death but not in circulatory-death or living-donor kidneys with similar donor characteristics.
As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using human ex-vivo precision-cut kidney slices and in-vitro podocytes. Notably, we showed that activation of Calpain-1 by Transforming-Growth Factor-β generated proteolytic fragments of Talin-1 that matched the degradation fragments detected in DBD preimplantation kidneys, also causing dysregulation of the actin cytoskeleton in human podocytes; events that were reversed by Calpain-1 inhibition. We provide initial evidence that cytoskeletal protein degradation in donor kidneys is a pathway that merits further investigation on how it impacts graft function in kidney transplantation.
Original languageEnglish
JournalAmerican Journal of Transplantation
Early online date8 Dec 2021
DOIs
Publication statusE-pub ahead of print - 8 Dec 2021

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