Albumin-bound fatty acids but not albumin itself alter redox balance in tubular epithelial cells and induce a peroxide-mediated redox-sensitive apoptosis
Albumin-bound fatty acids but not albumin itself alter redox balance in tubular epithelial cells and induce a peroxide-mediated redox-sensitive apoptosis
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DOI：
10.1152/ajprenal.00484.2013
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发表时间：
2014-04-01
影响因子：
4.2
通讯作者：
Stadler, Krisztian
中科院分区：
文献类型：
--
作者：
Ruggiero, Christine;Elks, Carrie M.;Stadler, Krisztian
蛋白尿与代谢综合征和糖尿病有关。它与慢性肾脏疾病的进展相关，特别是与肾小管萎缩相关。肥胖患者白蛋白上的脂肪酸负荷显著增加，为近端小管提供促炎环境。然而，鲜为人知的是，在氧化还原环境中的脂肪酸过载的变化，以及如何氧化还原敏感机制介导细胞死亡。在这里，我们表明，白蛋白与脂肪酸杂质或共轭棕榈酸酯，但不是白蛋白本身损害线粒体和细胞的活力，膜电位和呼吸。脂肪酸超载导致氧化还原失衡，使抗氧化蛋白peroxiredoxin 2失活，并通过氧化还原敏感的pJNK/caspase-3途径引起过氧化物介导的细胞凋亡。用过氧化物氧还蛋白2转染肾小管细胞具有保护作用并减轻凋亡。线粒体脂肪酸进入和神经酰胺合成调节剂表明，线粒体β氧化，而不是神经酰胺合成可能调节脂毒性作用对肾小管细胞存活。这些结果表明，白蛋白超载的脂肪酸，但不是白蛋白本身改变氧化还原环境中的小管，诱导过氧化物介导的氧化还原敏感性细胞凋亡。因此，降低循环脂肪酸水平可能是蛋白尿疾病中保持氧化还原平衡和预防肾小管细胞损伤的重要因素。
Albuminuria is associated with metabolic syndrome and diabetes. It correlates with the progression of chronic kidney disease, particularly with tubular atrophy. The fatty acid load on albumin significantly increases in obesity, presenting a proinflammatory environment to the proximal tubules. However, little is known about changes in the redox milieu during fatty acid overload and how redox-sensitive mechanisms mediate cell death. Here, we show that albumin with fatty acid impurities or conjugated with palmitate but not albumin itself compromised mitochondrial and cell viability, membrane potential and respiration. Fatty acid overload led to a redox imbalance which deactivated the antioxidant protein peroxiredoxin 2 and caused a peroxide-mediated apoptosis through the redox-sensitive pJNK/caspase-3 pathway. Transfection of tubular cells with peroxiredoxin 2 was protective and mitigated apoptosis. Mitochondrial fatty acid entry and ceramide synthesis modulators suggested that mitochondrial beta oxidation but not ceramide synthesis may modulate lipotoxic effects on tubular cell survival. These results suggest that albumin overloaded with fatty acids but not albumin itself changes the redox environment in the tubules, inducing a peroxide-mediated redox-sensitive apoptosis. Thus, mitigating circulating fatty acid levels may be an important factor in both preserving redox balance and preventing tubular cell damage in proteinuric diseases.