De Vecchi E, Lubatti L, Beretta C, Ferrero S, Rinaldi P, Galli Kienle M, Trazzi R, Paroni R
Department of Laboratory Medicine, IRCCS H San Raffaele, Milan, Italy.
Kidney Int. 1998 Sep;54(3):857-63. doi: 10.1046/j.1523-1755.1998.00072.x.
In a prior study the 21-aminosteroid (lazaroid) U74389F provided in vivo protection from oxidative stress when used as a preventive therapy in ischemia-reperfusion injury in the kidney. As the cell membrane is the principal site for lipoperoxidation, in the current study the very lipophilic 2-methylaminochroman U83836E, a recently developed lazaroid, was administered to rats at 3 mg/kg before renal ischemia-reperfusion. In addition to the biochemical parameters, the renal function and the histological appearance were carefully evaluated.
Glutathione, adenine nucleotides and lipid peroxidation products were determined in kidneys reperfused for 2 and 24 hours after 90 minutes of ischemia. Renal function was assessed by plasma creatinine, and renal injury by histological examination.
Reperfusion-induced glutathione oxidation, expressed as an oxidized-to-total glutathione ratio, was significantly attenuated both after 2 and 24 hours of reperfusion by treatment with U83836E. Adenosine triphosphate (ATP) was still significantly depleted after 24 hours in the control group, while at the same time treated animals had already recovered to baseline values. Lipid peroxidation products were significantly lower in lazaroid-groups both after 2 and 24 hours of reperfusion. Renal function after 24 hours of reperfusion was notably better in the treated rats. Histological examination confirmed the protective action of the drug. After 24 hours the control group showed large areas of parenchymal hemorrhage and necrosis with dilated tubules and blood vessel thrombosis, while treated animals showed small necrotic areas with a background of mild interstitial inflammatory cells.
Our results suggest that there is a protective effect of U83836E in ischemia-reperfusion injury, in that tissue damage due to oxidative stress is reduced, thus ameliorating renal function impairment.
在之前的一项研究中，21-氨基类固醇（拉扎罗类药物）U74389F在用于肾脏缺血再灌注损伤的预防性治疗时，可在体内提供抗氧化应激保护。由于细胞膜是脂质过氧化的主要部位，在本研究中，将亲脂性很强的2-甲基氨基色满U83836E（一种最近研发的拉扎罗类药物）在肾脏缺血再灌注前以3mg/kg的剂量给予大鼠。除了生化参数外，还仔细评估了肾功能和组织学表现。
在缺血90分钟后再灌注2小时和24小时的肾脏中测定谷胱甘肽、腺嘌呤核苷酸和脂质过氧化产物。通过血浆肌酐评估肾功能，通过组织学检查评估肾损伤。
用U83836E治疗后，再灌注2小时和24小时时，以氧化型谷胱甘肽与总谷胱甘肽的比率表示的再灌注诱导的谷胱甘肽氧化均显著减弱。对照组在24小时后三磷酸腺苷（ATP）仍显著消耗，而同时接受治疗的动物已恢复到基线值。再灌注2小时和24小时后，拉扎罗类药物组的脂质过氧化产物均显著降低。再灌注24小时后，治疗组大鼠的肾功能明显更好。组织学检查证实了该药物的保护作用。24小时后，对照组显示大面积实质出血和坏死，肾小管扩张和血管血栓形成，而治疗组动物显示小面积坏死区域，背景为轻度间质炎性细胞。
我们的结果表明，U83836E对缺血再灌注损伤有保护作用，因为它可减少氧化应激导致的组织损伤，从而改善肾功能损害。
