title: Protection Against Cold Storage-Induced Renal Tubular Cell Apoptosis.
abstract: BACKGROUND
  Prolonged cold storage (CS) of donor kidneys is associated with tubular cell apoptosis and caspase-3 activation. We have previously shown that pancaspase inhibition prevents CS-associated tubular apoptosis. Because of the nonspecific nature of pancaspase inhibitors, which block all caspases including proinflammatory caspase-1, the effect of specific caspase-3 inhibition during CS is unknown. X-linked inhibitor of apoptosis (XIAP) is the most potent naturally occurring specific inhibitor of caspase-3. We hypothesized that prolonged CS would decrease XIAP, whereas upregulation of XIAP with the novel compound UCF-101 would protect against caspase-3 activation and tubular cell apoptosis.
  
  
  METHODS
  LLC-PK1 tubular cells and whole kidneys from C57BL/6 mice were subjected to prolonged CS with or without UCF-101, and examined for XIAP, caspase-3, and tubular apoptosis.
  
  
  RESULTS
  Tubular cells subjected to prolonged CS in vitro demonstrated significantly decreased XIAP and significantly increased apoptosis, caspase-3 protein and activity. UCF-101 treatment significantly increased XIAP, significantly decreased capsase-3 protein and activity, and protected against apoptosis. To determine the therapeutic significance, whole kidneys were subjected to prolonged CS with UCF-101. UCF-101 significantly increased XIAP in donor kidneys and protected against apoptosis.
  
  
  CONCLUSIONS
  Prolonged CS of tubular cells in vitro and whole mouse kidneys ex vivo is associated with loss of XIAP and subsequent tubular cell apoptosis. UCF-101 protects against the loss of XIAP during prolonged CS both in vitro and ex vivo, and is associated with significantly reduced tubular cell apoptosis. UCF-101 may represent an attractive approach to improve organ preservation.
authors.affiliation: 1 Department of Renal Diseases and Hypertension, University of Colorado Denver, Denver, CO. 2 Renal Section, Denver Veterans Affairs Medical Center, Denver, CO. 3 Department of Pathology, University Zagreb SOM, Zagreb University Hospital Dubrava, Zagreb, Croatia.
authors.forename: Swati
authors.initials: S
authors.lastname: Jain
authors.forename: Daniel
authors.initials: D
authors.lastname: Keys
authors.forename: Danica
authors.initials: D
authors.lastname: Ljubanovic
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
authors.forename: Alkesh
authors.initials: A
authors.lastname: Jani
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D050377:Cold Ischemia / Q000009:adverse effects*; D019610:Cytoprotection; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018374:LLC-PK1 Cells; D008810:Mice, Inbred C57BL; D009392:Nephrectomy; D009926:Organ Preservation / Q000379:methods*; D011744:Pyrimidinones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D013871:Thiones / Q000494:pharmacology*
chemical_list: C107521:Birc4 protein, mouse; D061945:Caspase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D011744:Pyrimidinones; D013871:Thiones; C501517:UCF 101; C505409:Casp3 protein, mouse; D053148:Caspase 3