Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Eur J Pharmacol. 2012 Apr 15;681(1-3):94-9. doi: 10.1016/j.ejphar.2012.01.042. Epub 2012 Feb 9.
Delayed graft function secondary to ischemia/reperfusion injury has been shown to be associated with increased rate of allograft failure following kidney transplantation. Previously, we have shown that chronic lithium pretreatment protects kidney against ischemia/reperfusion injury. In the present study we aimed to examine the effects of acute lithium administration on the renal ischemia/reperfusion injury in rat. Ischemia/reperfusion injury was induced by clamping left renal pedicle for 60 min, two weeks after right nephrectomy. The mechanism of lithium-mediated renoprotection was explored by combined use of lithium and nitro-l-arginine methyl ester (L-NAME) (non-selective nitric oxide synthase inhibitor) and/or indomethacin (non-selective cyclooxygenase pathway inhibitor). Lithium-treated animals were given 40 mg/kg lithium chloride intraperitoneally, 30 min before ischemia. To investigate the role of nitric oxide and cyclooxygenase pathways in renoprotective effect of lithium, L-NAME and/or indomethacin were administered before lithium injection. Serum creatinine, blood urea nitrogen, and renal histology were assessed after 24h of reperfusion. Lithium preconditioning significantly reduced creatinine and blood urea nitrogen (P<0.001) and improved renal histology. Administration of L-NAME completely reversed renoprotective effect of lithium. In contrast indomethacin significantly potentiated the lithium renoprotection. Moreover, co-administration of L-NAME and indomethacin completely abolished the protective effects of lithium. The results show that a single dose of lithium significantly improves renal function following ischemia/reperfusion injury. In conclusion, the ability of lithium to enhance renal tissue tolerance against ischemia/reperfusion injury suggests a potential clinical application in the setting of kidney transplantation. However, more detailed investigations are required before any definite conclusion.
缺血/再灌注损伤导致的移植物功能延迟已被证明与肾移植后移植物衰竭的发生率增加有关。此前，我们已经表明，慢性锂预处理可保护肾脏免受缺血/再灌注损伤。在本研究中，我们旨在研究急性锂处理对大鼠肾缺血/再灌注损伤的影响。缺血/再灌注损伤通过夹闭左肾蒂 60 分钟来诱导，在右肾切除两周后进行。通过联合使用锂和硝基-L-精氨酸甲酯（非选择性一氧化氮合酶抑制剂）和/或吲哚美辛（非选择性环氧化酶途径抑制剂）来探索锂介导的肾保护机制。锂处理的动物在缺血前 30 分钟给予 40mg/kg 氯化锂腹膜内注射。为了研究一氧化氮和环氧化酶途径在锂的肾保护作用中的作用，在注射锂之前给予 L-NAME 和/或吲哚美辛。再灌注 24 小时后评估血清肌酐、血尿素氮和肾组织学。锂预处理显著降低了肌酐和血尿素氮（P<0.001），并改善了肾组织学。给予 L-NAME 完全逆转了锂的肾保护作用。相比之下，吲哚美辛显著增强了锂的肾保护作用。此外，L-NAME 和吲哚美辛的联合给药完全消除了锂的保护作用。结果表明，单次剂量的锂可显著改善缺血/再灌注损伤后的肾功能。总之，锂增强肾组织对缺血/再灌注损伤的耐受性的能力表明其在肾移植中的潜在临床应用。然而，在得出任何明确结论之前，还需要进行更详细的研究。
