The role of heme oxygenase 1 in rapamycin-induced renal dysfunction after ischemia and reperfusion injury
The role of heme oxygenase 1 in rapamycin-induced renal dysfunction after ischemia and reperfusion injury
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DOI：
10.1038/sj.ki.5001893
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发表时间：
2006-11-01
影响因子：
19.6
通讯作者：
Camara, N. O. S.
中科院分区：
文献类型：
--
作者：
Goncalves, G. M.;Cenedeze, M. A.;Camara, N. O. S.
缺血再灌注损伤（IRI）是自体肾和移植肾急性肾功能衰竭的主要病因。在移植领域，免疫抑制药物可能在急性移植物功能障碍中发挥额外的作用。雷帕霉素可能损害IRI后的肾再生。血红素加氧酶1（HO-1）是一种具有抗炎和抗凋亡作用的保护性基因。我们研究HO-1是否在已建立的IRI模型中在雷帕霉素诱导的肾功能不全中发挥作用。在经受45分钟的缺血之前，向小鼠施用雷帕霉素（3 mg/kg）。接受IRI的动物出现肾功能受损，在24小时达到峰值（2.05 +/-0.23 mg/dl），此后下降。与对照组（0.63 +/- 0.09mg/dl，P < 0.05）相比，雷帕霉素治疗组（2.30 +/- 0.33mg/dl）导致更多的肾功能障碍，并持续至再灌注后120小时（1.54 +/- 0.4mg/dl）。雷帕霉素延迟了肾小管再生，而在第5天，对照组的肾小管再生通常更高（68.53 +/- 2.30 vs 43.63 +/-3.11%，P < 0.05）。HO-1在IRI后显著上调，其表达甚至被雷帕霉素增强（1.32倍）。然而，通过钴原卟啉预先诱导HO-1改善了雷帕霉素引起的肾功能障碍，主要是在较晚的时间点。这些结果表明，在缺血损伤的器官中使用雷帕霉素也会对移植后恢复产生负面影响。HO-1表达的调节可能代表限制雷帕霉素急性毒性的可行方法。
Ischemia and reperfusion injury ( IRI) is the main etiology of acute renal failure in native and transplanted kidneys. In the transplantation field, immunosuppressive drugs may play an additional role in acute graft dysfunction. Rapamycin may impair renal regeneration post IRI. Heme oxygenase 1 ( HO-1) is a protective gene with anti-inflammatory and anti-apoptotic actions. We investigated whether HO-1 played a role in rapamycin-induced renal dysfunction in an established model of IRI. Rapamycin ( 3mg/kg) was administered to mice before being subjected to 45 min of ischemia. Animals subjected to IRI presented with impaired renal function that peaked at 24h ( 2.05 +/- 0.23mg/dl), decreasing thereafter. Treatment with rapamycin caused even more renal dysfunctions ( 2.30 +/- 0.33mg/dl), sustained up to 120 h after reperfusion ( 1.54 +/- 0.4mg/dl), when compared to the control ( 0.63 +/- 0.09mg/dl, P < 0.05). Rapamycin delayed tubular regeneration that was normally higher in the control group at day 5 ( 68.53 +/- 2.30 vs 43.63 +/- 3.11%, P < 0.05). HO-1 was markedly upregulated after IRI and its expression was even enhanced by rapamycin ( 1.32-fold). However, prior induction of HO-1 by cobalt protoporphyrin improved the renal dysfunction imposed by rapamycin, mostly at later time points. These results demonstrated that rapamycin used in ischemic-injured organs could also negatively affect post-transplantation recovery. Modulation of HO-1 expression may represent a feasible approach to limit rapamycin acute toxicity.