Doucet Carole, Milin Serge, Favreau Frederic, Desurmont Thibault, Manguy Emilie, Hébrard William, Yamamoto Yuriyo, Mauco Gérard, Eugene Michel, Papadopoulos Vassilios, Hauet Thierry, Goujon Jean Michel
Institut National de la Santé et de la Recherche Médicale U927, Université de Poitiers, Poitiers, France.
Am J Physiol Renal Physiol. 2008 Jul;295(1):F179-91. doi: 10.1152/ajprenal.00252.2007. Epub 2008 Apr 30.
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.
缺血再灌注损伤是肾移植功能障碍所涉及的主要非免疫过程之一。与其他供体的肾脏相比，非心脏跳动供体（NHBD）的肾脏延迟移植功能（DGF）发生率更高。原发性无功能和DGF是使用NHBD肾脏的主要障碍。我们使用NHBD移植猪模型，研究了FR167653（一种p38丝裂原活化蛋白激酶抑制剂）对经历热缺血（WI：1小时）和冷缺血（24小时）的肾脏恢复和修复的影响。我们的结果表明，添加FR167653可加快热缺血60分钟后近端肾小管细胞再生的动力学。与未治疗组相比，在接受FR167653治疗的肾脏中，缺氧诱导因子和血管内皮生长因子的表达也更为显著。此外，参与组织修复的外周型苯二氮䓬受体在FR167653治疗组中的表达增加。在3个月时，FR167653的保护作用伴随着长期炎症过程的减轻以及肾小管间质纤维化的发展受限，这与缺血诱导的重塑受限有关。这项研究表明，这种治疗方法可能有助于旨在提高NHBD肾移植质量的方案。此外，FR167653在限制早期损伤方面的有益作用与肾小管萎缩和间质纤维化发展的继发性减少有关，而肾小管萎缩和间质纤维化共同构成了肾移植失败的标志。当在热缺血前、冷藏期间和再灌注期间联合添加FR167653时，观察到了更有效的效果。
