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Title: | JNK signalling in human and experimental renal ischaemia/reperfusion injury. | Authors: | Polkinghorne K.R. ;Nikolic-Paterson D.J. ;Bennett B.L.;Friedman G.C.;Kanellis J.;Ma F.Y.;Kandane-Rathnayake R.;Dowling J.P. | Institution: | (Kanellis, Ma, Kandane-Rathnayake, Polkinghorne, Nikolic-Paterson) Department of Nephrology, Monash Medical Centre, Clayton, Melbourne, VIC, Australia (Kanellis, Ma, Polkinghorne, Nikolic-Paterson) Department of Medicine, Monash Medical Centre, Clayton, Melbourne, VIC, Australia (Dowling) Department of Anatomical Pathology, Monash Medical Centre, Clayton, Melbourne, VIC, Australia (Bennett, Friedman) Celgene, San Diego, CA, United States | Issue Date: | 12-Oct-2012 | Copyright year: | 2010 | Publisher: | Oxford University Press (Great Clarendon Street, Oxford OX2 6DP, United Kingdom) | Place of publication: | United Kingdom | Publication information: | Nephrology Dialysis Transplantation. 25 (9) (pp 2898-2908), 2010. Date of Publication: September 2010. | 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. © The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1093/ndt/gfq147 | PubMed URL: | 20368303 [http://www.ncbi.nlm.nih.gov/pubmed/?term=20368303] | ISSN: | 0931-0509 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/30930 | Type: | Article | Subjects: | male nonhuman priority journal prophylaxis protein function rat *reperfusion injury signal transduction CD44v antigen/ec [Endogenous Compound] creatinine/ec [Endogenous Compound] inducible nitric oxide synthase/ec [Endogenous Compound] intercellular adhesion molecule 1/ec [Endogenous Compound] macrophage elastase/ec [Endogenous Compound] *mitogen activated protein kinase/ec [Endogenous Compound] mitogen activated protein kinase inhibitor/dt [Drug Therapy] mitogen activated protein kinase inhibitor/pd [Pharmacology] tumor necrosis factor alpha/ec [Endogenous Compound] unclassified drug cc 401 kidney tubule damage/pc [Prevention] acute kidney failure/dt [Drug Therapy] acute kidney failure/pc [Prevention] animal experiment animal model article controlled study creatinine blood level enzyme activation enzyme inhibition epithelium cell human human cell human tissue immunohistochemistry kidney allograft kidney biopsy kidney function *kidney ischemia kidney transplantation kidney tubule damage/dt [Drug Therapy] human tissue immunohistochemistry kidney allograft kidney biopsy kidney function *kidney ischemia kidney transplantation kidney tubule damage / drug therapy / prevention male nonhuman priority journal prophylaxis protein function rat *reperfusion injury signal transduction animal model acute kidney failure / drug therapy / prevention animal experiment article controlled study creatinine blood level enzyme activation enzyme inhibition epithelium cell human human cell |
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