Normal Proteasome Function Is Needed to Prevent Kidney Graft Injury during Cold Storage Followed by Transplantation.

Area of Science:

• Nephrology
• Transplantation Biology
• Molecular Medicine

Background:

• Kidney transplantation is the primary treatment for end-stage kidney disease (ESKD).
• Donor organ quality is often compromised by cold storage (CS), impacting transplant success.
• Previous work indicated reduced renal proteasome function after CS and transplantation (CS + Tx).

Purpose of the Study:

• To investigate the mechanisms of proteasome dysfunction post-CS + Tx.
• To elucidate the role of the proteasome in kidney graft outcomes.

Main Methods:

• Utilized a rat model of CS + Tx.
• Analyzed proteasome subunit modification and assembly.
• Assessed reactive oxygen species (ROS) levels (nitrotyrosine).
• Investigated peroxynitrite effects on proteasome components in NRK cells.
• Examined the impact of proteasome inhibition on graft function.

Main Results:

• CS + Tx led to modification and aggregation of proteasome subunit Rpt6, alongside impaired assembly.
• Increased nitrotyrosine indicated elevated ROS (peroxynitrite) post-CS + Tx.
• Exogenous peroxynitrite decreased proteasome assembly chaperone PAC1 and subunit β5 in NRK cells.
• Proteasome inhibition in transplanted kidneys (without CS) mimicked CS + Tx effects on serum creatinine.

Conclusions:

• CS + Tx causes renal proteasome subunit dysregulation and assembly defects.
• Proteasome activity is vital for maintaining kidney graft function after cold storage and transplantation.