Jayle Christophe, Favreau Frederic, Zhang Kequiang, Doucet Carole, Goujon Jean Michel, Hebrard William, Carretier Michel, Eugene Michel, Mauco Gerard, Tillement Jean Paul, Hauet Thierry
Institut National de la Santé et de la Recherche Médicale E0324, Centre Hospitalier et Universitaire de Poitiers, Poitiers, France.
Am J Physiol Renal Physiol. 2007 Mar;292(3):F1082-93. doi: 10.1152/ajprenal.00338.2006.
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-1alpha) 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.
急性肾衰竭（ARF）通常是缺血再灌注损伤（IRI）的后果，且死亡率很高。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局。曲美他嗪（TMZ）是一种抗缺血药物。此前，我们已通过将TMZ直接添加到保存液中，验证了其对冷缺血猪肾模型的保护作用（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. 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）。在本研究中，我们旨在研究TMZ预处理（WI前24小时静脉注射5mg/kg）对WI 45、60和90分钟及再灌注在WI猪肾模型中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恢复并最小化缺血性肾损伤中常见的炎症反应，显著降低了45分钟，尤其是60和90分钟WI后的有害影响。与对照组（对照组和UNX组）相比，观察到：1）在TMZ治疗组中，缺氧诱导因子-1（HIF-1α）表达出现得更早且强度更高；2）再灌注后第一周IRI的减轻与参与肾小管修复过程的微管相关蛋白的更早、更强表达相关；3）肾小管间质纤维化减轻，尤其是在WI 60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。
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