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Background  Kidney injury associated with cold storage is a determinant of delayed graft function and the long-term outcome of transplanted kidneys, but the underlying mechanism remains elusive. We previously reported a role of protein kinase C- δ  (PKC δ ) in renal tubular injury during cisplatin nephrotoxicity and albumin-associated kidney injury, but whether PKC δ  is involved in ischemic or transplantation-associated kidney injury is unknown.    Methods  To investigate PKC δ ’s potential role in injury during cold storage–associated transplantation, we incubated rat kidney proximal tubule cells in University of Wisconsin (UW) solution at 4°C for cold storage, returning them to normal culture medium at 37°C for rewarming. We also stored kidneys from donor mice in cold UW solution for various durations, followed by transplantation into syngeneic recipient mice.    Results  We observed PKC δ  activation in both  in vitro  and  in vivo  models of cold-storage rewarming or transplantation. In the mouse model, PKC δ  was activated and accumulated in mitochondria, where it mediated phosphorylation of a mitochondrial fission protein, dynamin-related protein 1 (Drp1), at serine 616. Drp1 activation resulted in mitochondrial fission or fragmentation, accompanied by mitochondrial damage and tubular cell death. Deficiency of PKC δ  in donor kidney ameliorated Drp1 phosphorylation, mitochondrial damage, tubular cell death, and kidney injury during cold storage–associated transplantation. PKC δ  deficiency also improved the repair and function of the renal graft as a life-supporting kidney. An inhibitor of PKC δ ,  δ V1-1, protected kidneys against cold storage–associated transplantation injury.    Conclusions  These results indicate that PKC δ  is a key mediator of mitochondrial damage and renal tubular injury in cold storage–associated transplantation and may be an effective therapeutic target for improving renal transplant outcomes.

Protein Kinase C-δ Mediates Kidney Tubular Injury in Cold Storage–Associated Kidney Transplantation