Neutrophil peptidyl arginine deiminase-4 has a pivotal role in ischemia/reperfusion-induced acute kidney injury.
Neutrophil peptidyl arginine deiminase-4 has a pivotal role in ischemia/reperfusion-induced acute kidney injury.
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DOI：
10.1016/j.kint.2017.08.014
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发表时间：
2018-03
影响因子：
19.6
通讯作者：
Reeves WB
中科院分区：
文献类型：
--
作者：
Raup-Konsavage WM;Wang Y;Wang WW;Feliers D;Ruan H;Reeves WB
缺血再灌注是急性肾损伤(AKI)的常见原因。然而，肾功能突然丧失和组织损伤的机制仍未完全阐明。在这里，我们研究了精氨酸转化为瓜氨酸的肽基精氨酸脱亚胺酶-4(PAD4)在肾缺血/再灌注损伤中的作用，它在表观遗传调节和炎症中发挥作用。肾缺血再灌流后24小时，浸润性白细胞中PAD4的表达明显增强。这种诱导伴随着组蛋白H3的瓜氨酸化和在野生型小鼠肾脏中性粒细胞胞外陷阱的形成。相比之下，PAD4缺陷小鼠没有形成中性粒细胞细胞外陷阱，表达较低水平的促炎细胞因子，并对肾脏缺血/再灌注诱导的AKI有部分保护作用。此外，PAD4缺陷小鼠在缺血/再灌注48小时后恢复了肾功能，而野生型小鼠的肾功能则逐渐恶化。给予缺血前降解中性粒细胞胞外陷阱的DNase I或PAD特异性抑制剂YW3-56，可部分阻止肾缺血/再灌流诱导的AKI。值得注意的是，转移来自野生型而不是来自PAD4缺陷小鼠的中性粒细胞足以恢复肾缺血/再灌流后肾中性粒细胞细胞外陷阱的形成并损害肾功能。因此，中性粒细胞PAD4在肾缺血/再灌注性急性肾损伤中起关键作用。
Ischemia/reperfusion is a common cause of acute kidney injury (AKI). However, mechanisms underlying the sudden loss in kidney function and tissue injury remain to be fully elucidated. Here, we investigated the role of peptidyl arginine deiminase-4 (PAD4), which converts arginine to citrulline and plays a role in epigenetic regulation and inflammation, in renal ischemia/reperfusion injury. PAD4 expression was highly induced in infiltrating leukocytes 24 hours following renal ischemia and reperfusion. This induction was accompanied by citrullination of histone H3 and formation of neutrophil extracellular traps in kidneys of wild-type mice. By contrast, PAD4-deficient mice did not form neutrophil extracellular traps, expressed lower levels of pro-inflammatory cytokines and were partially protected from renal ischemia/reperfusion-induced AKI. Furthermore, PAD4-deficient mice recovered kidney function 48 hours after ischemia/reperfusion, whereas kidney function in the wild-type mice progressively worsened. Administration of DNase I, which degrades neutrophil extracellular traps or the PAD-specific inhibitor YW3-56 before ischemia, partially prevented renal ischemia/reperfusion-induced AKI. Notably, transfer of neutrophils from wild-type, but not from PAD4-deficient mice, was sufficient to restore renal neutrophil extracellular trap formation and impair kidney function following renal ischemia/reperfusion. Thus, neutrophil PAD4 plays a pivotal role in renal ischemia/reperfusion-induced AKI.
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DOI：
10.1084/jem.20100239
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li P;Li M;Lindberg MR;Kennett MJ;Xiong N;Wang Y
通讯作者：
Wang Y
影响因子：
8.6
作者：
Jang, Hye Ryoun;Rabb, Hamid
通讯作者：
Rabb, Hamid
DOI：
10.1016/b978-0-12-394309-5.00006-7
发表时间：
2012
影响因子：
--
作者：
Kalogeris, Theodore;Baines, Christopher P.;Krenz, Maike;Korthuis, Ronald J.
通讯作者：
Korthuis, Ronald J.
影响因子：
19.6
作者：
Deng, JP;Kohda, Y;Star, RA
通讯作者：
Star, RA
影响因子：
16.6
作者：
Kolaczkowska, Elzbieta;Jenne, Craig N.;Surewaard, Bas G. J.;Thanabalasuriar, Ajitha;Lee, Woo-Yong;Sanz, Maria-Jesus;Mowen, Kerri;Opdenakker, Ghislain;Kubes, Paul
通讯作者：
Kubes, Paul