Journal Article

JNK signalling in human and experimental renal ischaemia/reperfusion injury

John Kanellis, Frank Y. Ma, Rangi Kandane-Rathnayake, John P. Dowling, Kevan R. Polkinghorne, Brydon L. Bennett, Glenn C. Friedman and David J. Nikolic-Paterson

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 25, issue 9, pages 2898-2908
Published in print September 2010 | ISSN: 0931-0509
Published online April 2010 | e-ISSN: 1460-2385 | DOI:
JNK signalling in human and experimental renal ischaemia/reperfusion injury

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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.

Keywords: apoptosis; c-Jun; ischaemia/reperfusion; kidney transplant; macrophage

Journal Article.  5704 words.  Illustrated.

Subjects: Nephrology

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