Ishizuka S
First Department of Internal Medicine, Kyorin University, School of Medicine, Tokyo, Japan.
Nihon Jinzo Gakkai Shi. 1996 Feb;38(2):65-73.
It is an established fact that animals recovering from prior acute renal failure (ARF) are resistant to subsequent renal failure challenge with the same toxic agents, although the detailed mechanisms responsible for this phenomenon remain unclear. In this study, the mechanism underlying acquired resistance to gentanmicin (GM) was investigated from the viewpoint of kidney tissue enzymology. Sprague-Dawley rats (N = 40) were administered GM subcutaneously at the dose of 80mg/day consecutively for 40 days. Blood urea nitrogen (BUN) reached the maximum mean concentration of 36 mg/dl on day 14. Thereafter, it decreased to a level within the normal range on day 21. The change in fractional excretion of sodium (FENa) showed a curve virtually identical to the change in BUN. In renal tissue, the elevation of malondialdehyde (MDA) levels was transient during continued administration of GM. The shingomyelin (SPH)/phosphatidylcholine (PC) ratio significantly decreased on day 4, but there was no marked change thereafter. The levels of total phospholipids (PLs), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) increased, whereas SPH decreased mostly on day 4. The levels of phosphatidylinositol (PI) showed a continued fall during the 40 days of the experiment. On day 40, these changes in composition recovered. Phospholipase A2 (PLA2) activities decreased gradually, whereas a distinct increase in phospholipase C (PLC) activity was maintained after day 21. Furthermore, glutathione (GSH) levels also showed two distinct cycles of decrease and increase. PLs levels correlated well with PLC activities. It was concluded that accelerated lipid peroxidation occurs early in the course of GM administration and enhances changes in the phospholipid composition, which has an influence on membrane fluidity. Thus, acquired resistance to ARF induced by GM may be due to the supply of GSH and the maintenance of alteration in phospholipid composition, which are induced by PLC activities.
虽然导致这一现象的详细机制尚不清楚，但动物从先前的急性肾衰竭（ARF）中恢复后，对随后用相同毒性剂引发的肾衰竭具有抗性，这是一个既定事实。在本研究中，从肾组织酶学的角度研究了对庆大霉素（GM）获得性抗性的潜在机制。将40只Sprague-Dawley大鼠连续40天皮下注射GM，剂量为80mg/天。血尿素氮（BUN）在第14天达到最高平均浓度36mg/dl。此后，在第21天降至正常范围内。钠分数排泄（FENa）的变化显示出与BUN变化几乎相同的曲线。在肾组织中，持续给予GM期间丙二醛（MDA）水平的升高是短暂的。鞘磷脂（SPH）/磷脂酰胆碱（PC）比值在第4天显著降低，但此后没有明显变化。总磷脂（PLs）、磷脂酰胆碱（PC）和磷脂酰乙醇胺（PE）水平升高，而SPH大多在第4天下降。磷脂酰肌醇（PI）水平在实验的40天内持续下降。在第40天，这些组成变化恢复。磷脂酶A2（PLA2）活性逐渐降低，而磷脂酶C（PLC）活性在第21天后持续显著增加。此外，谷胱甘肽（GSH）水平也呈现出两个明显的下降和上升周期。PLs水平与PLC活性密切相关。得出的结论是，在GM给药过程早期发生加速的脂质过氧化，并增强磷脂组成的变化，这对膜流动性有影响。因此，GM诱导的对ARF的获得性抗性可能归因于GSH的供应以及由PLC活性诱导的磷脂组成改变的维持。
