|Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
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.
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