Nephrology Section, General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Transplantation. 2011 Jan 27;91(2):176-82. doi: 10.1097/TP.0b013e3181fffff2.
Kidneys from brain-dead donors are cold preserved until transplanted. However, prolonged cold storage can contribute to allograft failure. Studies suggest that donor preconditioning with dopaminergics may reduce cold-ischemic transplant injury, but whether heme oxygenase (HO)-1 induction is an underlying mechanism is not known.
To test whether preconditioning with fenoldopam (FD) induce HO-1 and protect kidneys against cold storage injury and whether HO-1 plays a role in protection.
We used human renal proximal tubular epithelial cells, rat kidney transplants, and HO-1 null mice kidneys.
FD preconditioning of cells for 4 hr significantly protected against cell death from 24-hr cold hypoxia and was associated with a dose-dependent increase in HO-1 expression. In a syngeneic rat kidney transplant model, FD preconditioning for 18 hr markedly increased kidney HO-1 expression and protected kidneys against 24-hr cold-ischemic transplant injury. To test the role of HO-1, renal proximal tubular epithelial cells were treated with HO-1 small interfering RNA, followed by FD-preconditioning. Small interfering RNA inhibited the HO-1 messenger RNA expression and reversed the FD protection. Suspension of kidneys of HO-1 null and wild-type mice preconditioned with FD or saline were subjected to 24- and 48-hr cold storage. N-acetyl glucosaminidase, a specific tubular injury marker, was significantly lower in FD-preconditioned wild-type kidneys, but not in HO-1 null kidneys, suggesting a role for HO-1 in FD's preconditioning.
Our data suggest HO-1 induction as an underlying mechanism for FD preconditioning and support the idea of testing FD preconditioning in the clinical setting. Studies are required to determine the optimum FD-preconditioning protocol.
脑死亡供体的肾脏在移植前进行冷保存。然而，长时间的冷藏会导致移植物衰竭。研究表明，多巴胺能药物预处理供体可能会减少冷缺血性移植损伤，但血红素加氧酶 (HO)-1 诱导是否是潜在的机制尚不清楚。
测试芬多拉唑 (FD) 预处理是否诱导 HO-1 并保护肾脏免受冷保存损伤，以及 HO-1 是否在保护中发挥作用。
我们使用人肾近端管状上皮细胞、大鼠肾移植和 HO-1 缺失小鼠的肾脏。
FD 预处理细胞 4 小时可显著减轻 24 小时冷缺氧引起的细胞死亡，与 HO-1 表达的剂量依赖性增加相关。在同种异体大鼠肾移植模型中，FD 预处理 18 小时可显著增加肾脏 HO-1 表达，并保护肾脏免受 24 小时冷缺血性移植损伤。为了测试 HO-1 的作用，用 HO-1 小干扰 RNA 处理肾近端管状上皮细胞，然后进行 FD 预处理。小干扰 RNA 抑制 HO-1 信使 RNA 表达并逆转 FD 保护。用 FD 或生理盐水预处理的 HO-1 缺失和野生型小鼠的肾脏悬液进行 24 和 48 小时的冷藏。N-乙酰氨基葡萄糖苷酶，一种特定的管状损伤标志物，在 FD 预处理的野生型肾脏中显著降低，但在 HO-1 缺失的肾脏中没有降低，这表明 HO-1 在 FD 的预处理中起作用。
我们的数据表明 HO-1 诱导是 FD 预处理的潜在机制，并支持在临床环境中测试 FD 预处理的想法。需要研究来确定最佳的 FD 预处理方案。
