Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model
Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model
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DOI：
10.1152/ajprenal.00338.2006
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发表时间：
2007-03-01
影响因子：
4.2
通讯作者：
Hauet, Thierry
中科院分区：
文献类型：
--
作者：
Jayle, Christophe;Favreau, Frederic;Hauet, Thierry
急性肾衰竭（ARF）通常是缺血 - 再灌注损伤（IRI）的结果，并伴有高死亡率。热缺血（WI）是组织损伤的关键因素，缺血 - 再灌注（I/R）导致的组织破坏会影响早期和长期的功能结果。曲美他嗪（TMZ）是一种抗缺血药物。此前，我们已经通过直接在保存液中添加TMZ，在冷缺血猪肾模型中验证了其保护作用（Faure JP，Baumert H，Han Z，Goujon JM，Favreau F，Dutheil D，Petit I，Barriere M，Tallineau C，Tillement JP，Carretier M，Mauco G，Papadopoulos V，Hauet T.《生物化学与药理学》66：2241 - 2250，2003；Faure JP，Petit I，Zhang K，Dutheil D，Doucet C，Favreau F，Eugene M，Goujon JM，Tillement JP，Mauco G，Vandewalle A，Hauet T.《美国移植杂志》4：495 - 504，2004）。在本研究中，我们旨在研究在热缺血猪肾模型中，TMZ预处理（在WI前24小时静脉注射5mg/kg）对45分钟、60分钟和90分钟WI以及再灌注所造成损伤的潜在影响。与假手术（对照）和单侧肾切除动物（UNX）相比，TMZ预处理通过改善肾功能的恢复并使缺血性肾损伤中常见的炎症反应最小化，显著降低了WI 45分钟后，尤其是60分钟和90分钟后的有害影响。与对照组（对照组和UNX组）相比，观察到：1）缺氧诱导因子 - 1（HIF - 1α）在TMZ处理组中表达更早且强度更高；2）再灌注后第一周内IRI的降低与参与肾小管修复过程的stathmin更早且更强的表达相关；3）肾小管间质纤维化减少，尤其是在WI 60分钟和90分钟后。总之，TMZ使热缺血肾脏对单次I/R的有害影响更具抵抗力，并减少了早期和长期的后续损伤。
Acute renal failure ( ARF) is often the consequence of an ischemia-reperfusion injury ( IRI) and associated with high mortality. Warm ischemia ( WI) is a crucial factor of tissue damage, and tissue destruction led by ischemia-reperfusion ( I/ R) can impact the early and long- term functional outcome. Trimetazidine ( TMZ) is an anti- ischemic drug. Previously, we already verified its protective effect on a cold- ischemic pig kidney model by directly adding TMZ into the preservation solution ( Faure JP, Baumert H, Han Z, Goujon JM, Favreau F, Dutheil D, Petit I, Barriere M, Tallineau C, Tillement JP, Carretier M, Mauco G, Papadopoulos V, Hauet T. Biochem Pharmacol 66: 2241 - 2250, 2003; Faure JP, Petit I, Zhang K, Dutheil D, Doucet C, Favreau F, Eugene M, Goujon JM, Tillement JP, Mauco G, Vandewalle A, Hauet T. Am J Transplant 4: 495 - 504, 2004). In this study, we aimed to study the potential effect of TMZ pretreatment ( 5 mg/ kg iv 24 h before WI) on the injury caused by WI for 45, 60, and 90 min and reperfusion in a WI pig kidney model. Compared with sham- operated ( control) and uninephrectomized animals ( UNX), TMZ pretreatment significantly reduced deleterious effects after 45 min, and particularly 60 and 90 min, of WI by improving the recovery of renal function and minimizing the inflammatory response commonly prevalent in ischemic kidney injury. Compared with controls ( control group and UNX group), it was observed that 1) hypoxia- inducible factor-1 ( HIF-1 alpha) expression occurred earlier and with a higher intensity in the TMZ- treated groups; 2) the reduction of IRI during the first week following reperfusion was correlated with an earlier and greater expression of stathmin, which is involved in the process of tubular repair; and 3) the tubulointerstitial fibrosis was reduced, particularly after 60 and 90 min of WI. In conclusion, TMZ made the warm- ischemic kidneys more resistant to the deleterious impact of a single episode of I/ R and reduced early and long- term subsequent damage.