Development of new therapeutic modality for acute renal failure by the inhibition of apoptosis

肾缺血再灌注可导致肾上皮细胞损伤，称为缺血性急性肾功能衰竭(IARF)，是重症监护病房所有ARF的主要形式。IARF的损伤被认为是由于再灌注产生的活性氧物种(ROS)，这在一定程度上是由于微粒体细胞色素P450迅速释放血红素所致。IARF肾功能的可逆性依赖于肾功能的长短。再灌注前的缺血预处理，例如，超过60分钟的缺血导致不可逆的肾损害。我们发现，在单侧肾切除和对侧肾动脉结扎40min的可逆性IARF模型中，血红素氧合酶-1(HO-1)mRNA及其酶活性均显著升高。HO的特异性竞争性抑制剂锡中卟啉(SnMP)抑制HO活性后，细胞内血红素含量显著增加，肾功能加重。…因此，HO-1的诱导在IARF中氧化损伤所致的肾功能障碍的保护中起着重要作用。然而，很少有研究研究HO-1在体内特异性地诱导靶组织而不影响其他组织的效果。据报道，氯化锡(SnCl2)是一种肾脏特异性的HO活性诱导剂。本实验观察了SnCl2对IARF大鼠肾脏HO-1诱导及肾脏损伤的影响。SnCl2处理可特异性诱导大鼠肾脏近端肾小管上皮细胞HO-1mRNA和HO-1蛋白表达，但未见明显的细胞损伤。肾缺血前给予SnCl2可在转录和蛋白水平增加HO-1在IARF大鼠肾上皮细胞中的表达。SnCl2预处理可使肾小管上皮细胞损伤明显减轻，表现为血清肌酐和血尿素氮水平显著降低，使肾小管上皮细胞微球血红素浓度短暂降低。相反，SnMP对HO活性的抑制，导致微粒体中血红素浓度的增加，抵消了SnCl2预处理的有利作用。提示SnCl2可通过诱导肾上皮细胞特异性HO-1而改善IARF大鼠的肾脏损伤。这些发现还表明，HO-1的诱导在保护肾细胞免受血红素引起的氧化损伤中起着重要作用，肾脏特异性HO-1的表达在治疗这种疾病中是有用的。因此，单纯被认为是有毒的SnCl2，由于其高度的肾脏特异性HO-1诱导作用，可能为IARF提供一种新的治疗模式。较少

Renal ischemia followed by reperfusion is known to result in renal epithelial cell injury, called ischemic acute renal failure (IARF), the major form of ARF of all episodes in intensive care units. IARF injury is thought to be due to reactive oxygen species (ROS) generated by reperfusion, which has been shown in part due to a rapid release of heme from microsomal cytochrome P450. The reversibility of renal function in IARF depends on the length. of the ischemic pretreatment prior to reperfusion, e.g., longer than 60 min ischemia resulting in an irreversible renal damage. We found that both heme oxygenase-1 (HO-1) mRNA and its enzyme activity were significantly increased in the reversible IARF model with a unilateral nephrectomy and the ligation of contralateral renal artery for 40 min. Inhibition of HO activity by tin mesoporphyrin (Sn-MP), a specific competitive inhibitor of HO, resulted both in a marked increase in intracellular heme content, and in the aggravation of renal function. … More Thus, HO-1 induction, plays an important role in the protection of renal dysfunction due to oxidative damage in IARF. However, only few studies have examined the effect of induction of HO-1 specifically in the target tissue in vivo without affecting other tissues. Tin chloride (SnCl_2) was reported to be a kidney-specific inducer of HO activity. We examined the effect of SnCl_2 administration on renal HO-1 induction, and on the renal injury in rats with IARF. SnCl_2 treatment specifically induced HO-1 mRNA, and protein in the proximal tubular epithelial cells of the kidney without apparent cell injury in the rat. SnCl_2 treatment before renal ischemia augmented the induct ion of HO-1 in IARF rats both at transcriptional and protein levels in renal epithelial cells. SnCl_2 pretreatment, which resulted in a transient decrease in microsomal heme concentration, ameliorated the ischemic renal injury as judged by significant decreases in serum creatinine and blood urea nitrogen levels and lesser tubular epithelial cell injuries. In contrast, inhibition of HO activity by treatment with Sn-MP, which resulted in an increase in microsomal heme concentration, abolished the beneficial effect of SnCl_2 pretreatment. These findings indicate that SnCl_2 pretreatment significantly improves the renal injury in rats with IARF by virtue of its specific HO-1 induction in renal epithelial cells. These findings also indicate that HO-1 induction plays an important role in conferring prot ection on renal cells from oxidative damages caused by heme, and that kidney-specific HO-1 expression is useful in the treatment of such conditions. Thus, SnCl_2, which has been simply thought to be toxic, may offer a new mode of treatment of IARF, because of its highly kidney-specific HO-1 inducing property. Less