PDF(Pubmed)
Abstract：
Renal ischemia/reperfusion is a serious condition that not only causes acute kidney injury, a severe clinical syndrome with high mortality, but is also an inevitable part of kidney transplantation or other kidney surgeries. Alterations of oxygen levels during ischemia/reperfusion, namely hypoxia/reoxygenation, disrupt mitochondrial metabolism and induce structural changes that lead to cell death. A signature mitochondrial phospholipid, cardiolipin, with many vital roles in mitochondrial homeostasis, is one of the key players in hypoxia/reoxygenation-induced mitochondrial damage. In this study, we analyze the effect of hypoxia/reoxygenation on human renal proximal tubule epithelial cell (RPTEC) cardiolipins, as well as their metabolism and mitochondrial functions. RPTEC cells were placed in a hypoxic chamber with a 2% oxygen atmosphere for 24 h to induce hypoxia; then, they were replaced back into regular growth conditions for 24 h of reoxygenation. Surprisingly, after 24 h, hypoxia cardiolipin levels substantially increased and remained higher than control levels after 24 h of reoxygenation. This was explained by significantly elevated levels of cardiolipin synthase and lysocardiolipin acyltransferase 1 (LCLAT1) gene expression and protein levels. Meanwhile, hypoxia/reoxygenation decreased ADP-dependent mitochondrial respiration rates and oxidative phosphorylation capacity and increased reactive oxygen species generation. Our findings suggest that hypoxia/reoxygenation induces cardiolipin remodeling in response to reduced mitochondrial oxidative phosphorylation in a way that protects mitochondrial function.
摘要：
肾缺血/再灌注是一种严重的疾病，不仅会导致急性肾损伤，高死亡率的严重临床综合征,但也是肾脏移植或其他肾脏手术不可避免的一部分。缺血/再灌注期间氧水平的变化，即缺氧/复氧，破坏线粒体代谢并诱导导致细胞死亡的结构变化。一种标志性的线粒体磷脂，心磷脂,在线粒体稳态中具有许多重要作用，是缺氧/复氧诱导的线粒体损伤的关键参与者之一。在这项研究中,我们分析了缺氧/复氧对人肾近曲小管上皮细胞（RPTEC）心磷脂的影响，以及它们的新陈代谢和线粒体功能。将RPTEC细胞置于2％氧气气氛的缺氧室中24小时以诱导缺氧；然后，它们被替换回到正常的生长条件下24小时的复氧。令人惊讶的是,24小时后，缺氧心磷脂水平大幅增加，并在复氧后24小时保持高于对照水平。这可以通过心磷脂合酶和溶血心磷脂酰基转移酶1（LCLAT1）基因表达和蛋白质水平的显着升高来解释。同时,缺氧/复氧会降低ADP依赖的线粒体呼吸速率和氧化磷酸化能力，并增加活性氧的产生。我们的发现表明，缺氧/复氧诱导心磷脂重塑，以保护线粒体功能的方式减少线粒体氧化磷酸化。
