Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption.
Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption.
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DOI：
10.1016/j.freeradbiomed.2015.05.020
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发表时间：
2015-09
影响因子：
7.4
通讯作者：
McIntyre TM
中科院分区：
文献类型：
--
作者：
Latchoumycandane C;Nagy LE;McIntyre TM
细胞色素P450 2E1 （CYP2E1）诱导和乙醇在肝细胞中的氧化代谢可引起肝脏炎症和损伤。慢性酒精摄入也会引起肾功能障碍，这与酒精性肝炎的死亡率有关。肾脏是否直接受到乙醇的影响或继发于肝损伤尚不确定。我们发现CYP2E1在长期摄入改良Lieber-deCarli液体乙醇饮食的小鼠肾小管中被诱导。azelaoyl磷脂酰胆碱（azz - pc）是一种仅通过氧化截断多不饱和磷脂酰胆碱形成的非生物合成产物，乙醇喂养小鼠肾小管磷脂被氧化和碎片化。Az-PC刺激嗜中性粒细胞和肾小管大量表达的炎性PAF受体（PTAFR），使乙醇喂养小鼠肾内炎症细胞和含髓过氧化物酶的中性粒细胞蓄积明显迟滞。肾滤过减少和急性肾损伤生物标志物KIM-1在小管中的诱导与白细胞浸润时间相关。基因消融PTAFR可减少PTAFR配体的积累，减少白细胞对肾脏的浸润。在PTAFR - / -小鼠中，这种受体的缺失也抑制了氧化损伤和肾功能障碍，而不影响CYP2E1的诱导。中性粒细胞炎症是乙醇诱导肾损伤的原因，因为MPO - / -小鼠中性粒细胞过氧化物酶的丧失具有类似的保护作用。我们得出结论，肾小管中的乙醇分解代谢导致CYP2E1诱导、局部PTAFR配体形成、中性粒细胞浸润和激活的自我延续循环，导致髓过氧化物酶依赖性氧化和肾功能损害。肝细胞不表达PTAFR，因此这种氧化循环是肾脏对乙醇分解代谢的局部反应。
Cytochrome P450 2E1 (CYP2E1) induction and oxidative metabolism of ethanol in hepatocytes inflames and damages liver. Chronic ethanol ingestion also induces kidney dysfunction, which associates with mortality of alcoholic hepatitis. Whether kidney is directly affected by ethanol or is secondary to liver damage is not established. We found CYP2E1 was induced in kidney tubules of mice chronically ingesting a modified Lieber-deCarli liquid ethanol diet. Phospholipids of kidney tubules were oxidized and fragmented in ethanol fed mice with accumulation of azelaoyl phosphatidylcholine (Az-PC), a non-biosynthetic product formed only by oxidative truncation of polyunsaturated phosphatidylcholine. Az-PC stimulates the inflammatory PAF receptor (PTAFR) abundantly expressed by neutrophils and kidney tubules, and inflammatory cells and myeloperoxidase-containing neutrophils accumulated in kidney of ethanol fed mice after significant hysteresis. Decreased kidney filtration and induction of the Acute Kidney Injury biomarker KIM-1 in tubules temporally correlated with leukocyte infiltration. Genetic ablation of PTAFR reduced accumulation of PTAFR ligands, and reduced leukocyte infiltration into kidney. Loss of this receptor in PTAFR−/− mice also suppressed oxidative damage and kidney dysfunction without affecting CYP2E1 induction. Neutrophilic inflammation was responsible for ethanol-induced kidney damage because loss of neutrophil myeloperoxidase in MPO−/− mice was similarly protective. We conclude ethanol catabolism in renal tubules results in a self-perpetuating cycle of CYP2E1 induction, local PTAFR ligand formation, neutrophil infiltration and activation that leads to myeloperoxidase-dependent oxidation and damage to kidney function. Hepatocytes do not express PTAFR, so this oxidative cycle is a local response to ethanol catabolism in kidney.