title: Aprotinin improves kidney function and decreases tubular cell apoptosis and proapoptotic signaling after renal ischemia-reperfusion.
abstract: OBJECTIVE
  The purpose of the study was to determine the effects of aprotinin on (1) renal function, (2) apoptosis and apoptotic signaling, and (3) the inflammatory response of the kidney after ischemia-reperfusion injury.
  
  
  METHODS
  Male rats underwent a sham procedure or left renal ischemia for 1 hour. Rats were divided into three groups and received no reperfusion, reperfusion for 1 hour, or reperfusion for 24 hours. The animals undergoing ischemia received saline solution alone or aprotinin (60,000 kIU/kg). At the end of the experiment, a sample for serum creatinine was taken and the left kidney was harvested. The kidney was analyzed for expression of tumor necrosis factor alpha, interleukin 1beta, and interleukin 6 (enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction) and activation of p38 mitogen-activated protein kinase, caspase 3, and caspase 8 (Western blot). The kidney was assessed for apoptosis with enzyme-linked immunosorbent assay and by terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate nick-end labeling staining of tissue slides.
  
  
  RESULTS
  Aprotinin significantly decreased the rise in serum creatinine and apoptosis caused by ischemia-reperfusion. Aprotinin significantly reduced interleukin 1 and 6 messenger RNA production and showed a trend toward reducing tumor necrosis factor messenger RNA production after ischemia. Aprotinin also significantly reduced caspase 8 activation and showed a trend toward decreasing p38 mitogen-activated protein kinase activation after 1 hour of reperfusion.
  
  
  CONCLUSIONS
  These results suggest that aprotinin provides protection from renal ischemia-reperfusion injury. They also suggest that aprotinin may do so by affecting apoptotic signaling and inflammatory cytokine production. Aprotinin is a potential therapeutic measure in clinical situations where renal ischemia-reperfusion injury can be anticipated, provided adequate heparinization is possible.
authors.affiliation: Department of Surgery, Indiana University Medical Center, Indianapolis, Ind, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Kher
authors.forename: Kirstan K
authors.initials: KK
authors.lastname: Meldrum
authors.forename: Karen L
authors.initials: KL
authors.lastname: Hile
authors.forename: Meijing
authors.initials: M
authors.lastname: Wang
authors.forename: Ben M
authors.initials: BM
authors.lastname: Tsai
authors.forename: Mark W
authors.initials: MW
authors.lastname: Turrentine
authors.forename: John W
authors.initials: JW
authors.lastname: Brown
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D017209:Apoptosis; D007611:Aprotinin / Q000494:pharmacology*; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D051381:Rats; D015424:Reperfusion; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D007611:Aprotinin; D003404:Creatinine; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases