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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/F179    most recent 00252.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Doucet, C. Articles by Goujon, J. M. PubMed PubMed Citation Articles by Doucet, C. Articles by Goujon, J. M.

A p38 mitogen-activated protein kinase inhibitor protects against renal damage in a non-heart-beating donor model

¹Institut National de la Santé et de la Recherche Médicale U927, Université de Poitiers, Poitiers; ²Institut National de la Recherche Agronomique, GEPA, Laboratoire de Transplantation Expérimentale, Domaine Expérimental du Magneraud, Surgères; ³Research Department, Fujisawa Pharmaceutical, Osaka, Japan; ⁴Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, District of Columbia; and ⁵Centre Hospitalier Universitaire de Poitiers, Service d'Anatomie et Cytologie Pathologique et Unité de Pathologie Ultrasctructurale et Expérimentale, Poitiers, France

Submitted 30 May 2007 ; accepted in final form 24 April 2008

Ischemia-reperfusion injury is one of the central nonimmunologic processes involved in renal allograft dysfunction. Kidneys from non-heart beating donors (NHBD) exhibit higher rates of delayed graft function (DGF) than those from other donors. Primary nonfunction and DGF are the main barriers to the use of kidneys from NHBD. Using a pig model of NHBD transplantation, we studied the effect of FR167653 (a p38 MAP kinase inhibitor) on the recovery and reparation of kidneys exposed to both warm (WI: 1 h) and cold ischemia (24 h). Our results demonstrate that the addition of FR167653 increases the kinetics of proximal tubule cell regeneration after 60 min of WI. Hypoxia-inducible factor and vascular endothelial growth factor expression was also more important in FR167653-treated kidneys compared with those in nontreated groups. Also, expression of peripheral-type benzodiazepine receptor, involved in tissue repair, was increased in the FR167653-treated groups. At 3 mo, the protective effects of FR167653 were accompanied by a reduction of long-term inflammation process and tubulointerstitial fibrosis development associated with a limitation of ischemia-induced remodeling. This study suggests that such treatment may be useful in protocols aimed at improving the quality of renal transplants from NHBD. In addition, the beneficial role of FR167653 in limiting early injury is associated with secondary reduction in development of tubular atrophy and interstitial fibrosis which are together the hallmark of failing renal transplants. The more efficient effect was observed when FR167653 was added in combination before WI, during cold storage and reperfusion.

ischemia-reperfusion injury; angiogenesis; tissue repair; renal fibrosis