PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury
PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury
复制标题
DOI：
10.1038/s41589-023-01528-7
复制
发表时间：
2024-01-29
影响因子：
14.8
通讯作者：
Chen，Quan
中科院分区：
文献类型：
--
作者：
Zhang，Qianping;Sun，Tiantian;Chen，Quan
同步性铁下垂导致急性肾损伤（AKI）中肾元丢失。然而，肾小管损伤的同步铁下垂的传播信号和潜在机制尚不清楚。在这里，我们报道了血小板活化因子（PAF）和PAF样磷脂（PAF- lpls）介导同步性铁下沉并导致AKI。铁下垂中PAF和PAF- lpls的出现引起生物膜的不稳定，并提示邻近细胞的死亡。这种级联反应可以通过PAF乙酰水解酶（PAFAH2）或添加抗PAF抗体来抑制。基因敲除或药物抑制PAFAH2可增加PAF的产生，增强同步性铁吊，加重缺血/再灌注（I/R）诱导的AKI。值得注意的是，静脉注射野生型PAFAH2蛋白，而不是其酶失活突变体，可以防止同步小管细胞死亡、肾单位损失和AKI。我们的研究结果提供了对同步铁下垂机制的深入了解，并提出了AKI预防性干预的可能性。
Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLs in ferroptosis caused the instability of biomembranes and signaled the cell death of neighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II) (PAFAH2) or by addition of antibodies against PAF. Genetic knockout or pharmacological inhibition of PAFAH2 increased PAF production, augmented synchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI. Notably, intravenous administration of wild-type PAFAH2 protein, but not its enzymatically inactive mutants, prevented synchronized tubular cell death, nephron loss and AKI. Our findings offer an insight into the mechanisms of synchronized ferroptosis and suggest a possibility for the preventive intervention of AKI.