Zager R A, Iwata M, Conrad D S, Burkhart K M, Igarashi Y
Department of Medicine, University of Washington, Seattle, USA.
Kidney Int. 1997 Jul;52(1):60-70. doi: 10.1038/ki.1997.304.
Recent evidence indicates that a "sphingomyelin signaling pathway" exists: in response to heterogeneous influences, sphingomyelin is hydrolyzed, liberating ceramide, and subsequently its sphingoid base, sphingosine. Ceramide and sphingosine can influence diverse cellular processes, including cell differentiation, proliferation, protein trafficking, and apoptosis. Each of these processes have important implications for post-ischemic acute renal failure (ARF). However, sphingosine and ceramide expression during the induction of ischemic/reperfusion injury have not been previously assessed. To this end, CD-1 mice were subjected to 45 minutes of unilateral renal ischemia +/- reperfusion, followed by cortical sphingosine, ceramide, and sphingomyelin assessments. Contralateral kidneys served as controls. Ischemia caused approximately 50% sphingosine and ceramide decrements. During reperfusion, sphingosine rebounded to normal values. Conversely, ceramide rose to, and was maintained at, supranormal levels (approximately 175% of controls). Subsequent studies performed with hypoxic or oxygenated isolated proximal tubules suggested that these changes: (1) had a multifactorial basis; (2) were partially simulated by enhanced PLA2 activity; (3) and were dissociated from alterations in net sphingomyelin content. To assess the potential pathogenic relevance of the documented ceramide increments, cultured human proximal tubule (HK-2) cells were subjected to ATP depletion/Ca2+ ionophore- or PLA2-induced attack with or without exogenous C2 ceramide loading. Ceramide worsened both forms of injury without exerting an independent lethal effect. Conversely, ceramide markedly attenuated arachidonic acid cytotoxicity. This occurred without any decrease in arachidonate uptake, suggesting a direct cytoprotective effect.
(1) sphingosine and ceramide fluxes are hallmarks of early ischemic/reperfusion injury; (2) these changes occur via divergent metabolic pathways; and (3) that ceramide increments can affect divergent injury pathways, and that sphingosine and ceramide have potent cell signaling effects, suggest that the currently documented sphingosine/ ceramide fluxes could have important implications for the induction phase and evolution of post-ischemic ARF.
最近的证据表明存在一条“鞘磷脂信号通路”：在异质性影响下，鞘磷脂被水解，释放出神经酰胺，随后释放出其鞘氨醇碱——鞘氨醇。神经酰胺和鞘氨醇可影响多种细胞过程，包括细胞分化、增殖、蛋白质运输和细胞凋亡。这些过程中的每一个对缺血后急性肾衰竭（ARF）都有重要意义。然而，此前尚未评估缺血/再灌注损伤诱导过程中鞘氨醇和神经酰胺的表达情况。为此，对CD-1小鼠进行45分钟的单侧肾脏缺血加/减再灌注，随后进行皮质鞘氨醇、神经酰胺和鞘磷脂评估。对侧肾脏作为对照。缺血导致鞘氨醇和神经酰胺减少约50%。在再灌注期间，鞘氨醇反弹至正常值。相反，神经酰胺升至超正常水平并维持在该水平（约为对照的175%）。随后对缺氧或氧合的离体近端小管进行的研究表明，这些变化：（1）有多种因素基础；（2）部分由增强的磷脂酶A2活性模拟；（3）与鞘磷脂净含量的改变无关。为评估所记录的神经酰胺增加的潜在致病相关性，对培养的人近端小管（HK-2）细胞进行ATP耗竭/钙离子载体或磷脂酶A2诱导的攻击，同时或不加载外源性C2神经酰胺。神经酰胺会加重两种形式的损伤，但不产生独立的致死作用。相反，神经酰胺显著减弱花生四烯酸的细胞毒性。这一过程中花生四烯酸摄取没有任何减少，表明存在直接的细胞保护作用。
（1）鞘氨醇和神经酰胺通量是早期缺血/再灌注损伤的标志；（2）这些变化通过不同的代谢途径发生；（3）神经酰胺增加可影响不同的损伤途径，且鞘氨醇和神经酰胺具有强大的细胞信号作用，这表明目前所记录的鞘氨醇/神经酰胺通量可能对缺血后ARF的诱导阶段和发展具有重要意义。
