title: JNK signalling in human and experimental renal ischaemia/reperfusion injury.
abstract: BACKGROUND
  Ischaemia/reperfusion (I/R) is an important factor in delayed graft function in renal transplantation and is a determinant of long-term graft outcome. This study examined the role of c-Jun N-terminal kinase (JNK) signalling in human and experimental renal I/R injury.
  
  
  METHODS
  Biopsies obtained 15-20 min after reperfusion of human renal allografts were examined for JNK signalling by immunostaining for phospho-c-Jun. To examine the pathologic role of JNK signalling, a selective JNK inhibitor (CC-401) was administered to rats before or after the induction of a 30-min period of bilateral renal ischaemia followed by reperfusion. Renal function and tubular damage were analysed.
  
  
  RESULTS
  Substantial JNK activation was evident in tubular epithelial cells in kidneys from deceased donors (n = 30) which was less prominent in kidneys from live donors (n = 7) (44.6 +/- 24.8% vs 29.1 +/- 20% p-c-Jun+, respectively; P < 0.05), whereas biopsies of thin basement membrane disease exhibited little, or no, p-c-Jun staining. The degree of p-c-Jun staining correlated with ischaemic time in deceased donor allografts, but not with graft function. Administration of CC-401 to rats prior to bilateral renal I/R prevented acute renal failure and largely prevented tubular damage, leucocyte infiltration and upregulation of pro-inflammatory molecules. However, delaying CC-401 treatment until 1 h after reperfusion (after the peak of JNK activation) had no protective effect.
  
  
  CONCLUSIONS
  We have identified acute activation of the JNK signalling pathway following I/R in human kidney allografts. Experimental studies indicate that blockade of JNK signalling, commenced prior to this activation, can prevent acute tubular necrosis and renal dysfunction secondary to I/R injury.
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Melbourne, Victoria, Australia. john.kanellis@med.monash.edu.au
authors.forename: John
authors.initials: J
authors.lastname: Kanellis
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Ma
authors.forename: Rangi
authors.initials: R
authors.lastname: Kandane-Rathnayake
authors.forename: John P
authors.initials: JP
authors.lastname: Dowling
authors.forename: Kevan R
authors.initials: KR
authors.lastname: Polkinghorne
authors.forename: Brydon L
authors.initials: BL
authors.lastname: Bennett
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Friedman
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications / Q000517:prevention & control* / Q000628:therapy; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D006801:Humans; D007124:Immunoenzyme Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D047069:Pyrazolones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C525250:CC 401; D018836:Inflammation Mediators; D047069:Pyrazolones; D012333:RNA, Messenger; D048031:JNK Mitogen-Activated Protein Kinases