Synergistic renal protection by combining alkaline-diuresis with lipid peroxidation inhibitors in rhabdomgolysis: Possible interaction between oxidant and non-oxidant mechanisms
Synergistic renal protection by combining alkaline-diuresis with lipid peroxidation inhibitors in rhabdomgolysis: Possible interaction between oxidant and non-oxidant mechanisms
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DOI：
10.1093/oxfordjournals.ndt.a027352
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发表时间：
1996-04-01
影响因子：
6.1
通讯作者：
Tachikawa, H
中科院分区：
文献类型：
--
作者：
Salahudeen, AK;Wang, CY;Tachikawa, H
背景和目的。血红素蛋白除了引起肾小管阻塞外，还可能通过血红素铁介导的脂质过氧化过程导致横纹肌溶解引起的肾损伤。在本研究中，我们将脂质过氧化抑制剂、21-氨基类固醇（21-AS）和液体碱性甘露醇（FAM）利尿剂的联合治疗与单独使用其中任何一种进行比较，以确定联合治疗的疗效并描述脂质过氧化和管型形成的作用。方法和结果。利用拉曼光谱，我们在体外证实了 21-AS 抑制铁诱导的脂肪酸过氧化的能力。然后将 21-AS 给予因甘油诱导的横纹肌溶解而发生肾衰竭的大鼠。尽管21-AS抑制横纹肌溶解引起的血浆和肾脏脂质过氧化，但肾脏保护并不完全。施用 FAM 抑制管型形成可提供更好的肾脏保护。然而，当这些疗法联合起来抑制脂质过氧化和管型形成时，就会产生协同的肾功能保护作用。这伴随着对肾脏和血浆脂质过氧化以及肾小管坏死和管型形成的最大抑制。与联合治疗相比，单独使用 FAM 治疗，尽管体积相同，但伴有更高的肾小管坏死和管型形成。结论。在横纹肌溶解症中，将脂质过氧化抑制剂与液体碱性利尿剂相结合，可进一步降低肾脂质过氧化、肾小管坏死和管型形成，并协同限制肾功能障碍（i）支持脂质过氧化在横纹肌溶解症 ARF 病理生理学中的作用，（ii）强调肾小管内血红素潴留的作用，肾小管内血红素潴留是肾小管阻塞的原因，也是大量铁的来源，可能与脂质有关过氧化，(iii) 增加了非氧化和氧化机制之间相互作用的可能性。
Background and purpose. Heme-proteins, besides causing renal tubular obstruction, may contribute to rhabdomyolysis-induced renal injury through a heme-iron-mediated lipid peroxidation process. In the present study, we compared the combined therapy of a lipid peroxidation inhibitor, 21-aminosteroid (21-AS) and fluid-alkaline-mannitol (FAM) diuresis with either of them alone to determine the efficacy of the combination therapy and to delineate the roles of lipid peroxidation and cast formation.Methods and results. Employing Raman spectroscopy, we confirmed in vitro the ability of 21-AS to inhibit iron-induced fatty acid peroxidation. 21-AS was then administered to rats developing renal failure from glycerol-induced rhabdomyolysis. Although 21-AS inhibited rhabdomyolysis-induced plasma and renal lipid peroxidation, renal protection was incomplete. Administration of FAM to inhibit cast formation afforded a better renal protection. However, when these therapies were combined to inhibit both lipid peroxidation and cast formation, there was a synergistic renal functional protection. This was accompanied by a maximum inhibition of renal and plasma lipid peroxidation, as well as, renal tubular necrosis and cast formation. Compared to combination therapy, FAM therapy alone, despite identical volume, was accompanied by a higher tubular necrosis and cast formation.Conclusions. That combining a lipid peroxidation inhibitor with fluid-alkaline diuresis in rhabdomyolysis further lowers renal lipid peroxidation, tubular necrosis and cast formation and synergistically limits renal dysfunction (i) supports a role for lipid peroxidation in the pathophysiology of rhabdomyolysis ARF, (ii) underscores the role of intratubular heme retention, a cause for tubular obstruction as well a source for prodigious amount of iron, likely involved in the lipid peroxidation, and (iii) raises the possibility of interactions between non-oxidant and oxidant mechanisms.