Endothelial peroxisomal dysfunction and impaired pexophagy promotes oxidative damage in lipopolysaccharide-induced acute kidney injury.
Endothelial peroxisomal dysfunction and impaired pexophagy promotes oxidative damage in lipopolysaccharide-induced acute kidney injury.
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DOI：
10.1089/ars.2012.4768
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发表时间：
2013-06
影响因子：
6.6
通讯作者：
R. Vasko;Brian B. Ratliff;S. Bohr;E. Nadel;Jun Chen;S. Xavier;P. Chander;M. Goligorsky
中科院分区：
文献类型：
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作者：
R. Vasko;Brian B. Ratliff;S. Bohr;E. Nadel;Jun Chen;S. Xavier;P. Chander;M. Goligorsky
目的 我们研究了（a）内毒素应激如何影响过氧化物酶体功能和过氧化物酶体自噬降解，（b）溶酶体和过氧化物酶体自噬的叠加功能障碍如何改变对脂多糖（LPS）的反应，以及（c）过氧化物酶体对肾损伤的贡献机制。为了实现这一目标，我们在体内使用了溶酶体缺陷型 Lyst 小鼠，在体外使用了原代内皮细胞，并将反应与野生型 (WT) 同窝小鼠进行了比较。结果 LPS 在 WT 小鼠中诱导 pexophagagic 降解，随后过氧化物酶体增殖，而在 Lyst 小鼠中则被消除。 Lyst 小鼠表现出过氧化氢酶活化受损，与保留的过氧化氢生成 β-氧化作用一起导致氧化还原不平衡。 LPS 治疗诱导 Lyst 小鼠炎症反应加剧、氧化损伤增加并加重肾损伤。类似地，与体内一样，在溶酶体附近的过氧化物酶体密度降低的支持下，LPS 激活的溶酶体 (LYS) 自噬和体外短暂抑制过氧化物酶体。溶酶体缺陷细胞中的过氧化物酶体动力学也被消除，这些细胞积累了功能受损和细胞器内氧化还原失衡的过氧化物酶体。创新 我们证明了 pexophagy 是对内毒素损伤的默认反应。然而，当LYS功能障碍（慢性疾病的常见伴随）叠加时，过氧化物酶体的循环和功能受到损害，并且产生过氧化氢的β-氧化和过氧化氢解毒过氧化氢酶之间的不平衡随之而来，最终导致过氧化物酶体倦怠。结论 我们的数据强烈表明，pexophagy（一种细胞机制本身）对于 LPS 暴露期间过氧化物酶体的功能维持至关重要。抑制自噬会导致过氧化物酶体受损、氧化还原不平衡和肾损伤加重。
AIMS We examined that (a) how the endotoxic stress affects peroxisomal function and autophagic degradation of peroxisomes-pexophagy, (b) how a superimposed dysfunction of lysosomes and pexophagy modifies responses to lipopolysaccharide (LPS), and (c) the mechanisms of peroxisomal contribution to renal injury. To accomplish this, we used lysosome-defective Lyst-mice in vivo and primary endothelial cells in vitro, and compared the responses with wild-type (WT) littermates. RESULTS LPS induced pexophagic degradation, followed by proliferation of peroxisomes in WT mice, which was abolished in Lyst-mice. Lyst-mice exhibited impaired activation of catalase, which together with preserved hydrogen peroxide-generating β-oxidation resulted in redox disequilibrium. LPS treatment induced a heightened inflammatory response, increased oxidative damage, and aggravated renal injury in Lyst-mice. Similarly, as in vivo, LPS-activated lysosomal (LYS) pexophagy and transiently repressed peroxisomes in vitro, supported by reduced peroxisomal density in the vicinity of lysosomes. Peroxisomal dynamics was also abolished in lysosome-defective cells, which accumulated peroxisomes with compromised functions and intraorganellar redox imbalance. INNOVATION We demonstrated that pexophagy is a default response to endotoxic injury. However, when LYS dysfunction (a frequent companion of chronic diseases) is superimposed, recycling and functioning of peroxisomes are impaired, and an imbalance between hydrogen peroxide-generating β-oxidation and hydrogen peroxide-detoxifying catalase ensues, which ultimately results in peroxisomal burnout. CONCLUSION Our data strongly suggest that pexophagy, a cellular mechanism per se, is essential in functional maintenance of peroxisomes during LPS exposure. Inhibition of pexophagy results in accumulation of impaired peroxisomes, redox disequilibrium, and aggravated renal damage.