DHHC21 deficiency attenuates renal dysfunction during septic injury.
DHHC21 deficiency attenuates renal dysfunction during septic injury.
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DOI：
10.1038/s41598-021-89983-x
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发表时间：
2021-05-27
影响因子：
4.6
通讯作者：
Yuan SY
中科院分区：
文献类型：
--
作者：
Yang X;Zheng E;Ma Y;Chatterjee V;Villalba N;Breslin JW;Liu R;Wu MH;Yuan SY
肾功能不全是脓毒性损伤最常见的并发症之一。脓毒性损伤诱导的肾功能不全的一个关键因素是肾血管功能不全。蛋白质棕榈酰化作为一种新的调节血管功能。在这里，我们研究了棕榈酰酰基转移酶（PAT）-DHHC 21是否有助于脓毒性损伤诱导的肾功能不全，通过调节肾血流动力学。多光谱光声成像显示，盲肠结扎穿孔（CLP）诱导的脓毒性损伤导致肾脏排泄受损，这在DHHC 21功能缺陷（Zdhhc 21 dep/dep）小鼠中得到改善。DHHC 21缺乏减弱了CLP诱导的肾脏病理，其特征在于组织结构损伤和循环损伤标志物。重要的是，DHHC 21功能丧失导致CLP后更好地保留了肾灌注和氧饱和度。CLP引起的肾血流量减少在Zdhhc 21 dep/dep小鼠中也得到改善。CLP促进血管α1-肾上腺素能受体（α 1-adrenergicreceptor，α1AR）棕榈酰化及其下游效应子ERK的激活，而Zdhhc 21 dep/dep小鼠的α 1-AR棕榈酰化及其下游效应子ERK的激活减弱。血管反应性分析显示，与野生型小鼠相比，Zdhhc 21 dep/dep小鼠的肾动脉对α1AR激动剂苯丙氨酸的收缩反应降低。一致的是，抑制PAT与2-溴棕榈酸酯引起钝化的血管收缩反应，苯肾上腺素在小动脉分离自人肾脏。因此，DHHC 21通过促进α1AR棕榈酰化相关的血管收缩，在脓毒性损伤期间导致肾灌注和功能受损。
Renal dysfunction is one of the most common complications of septic injury. One critical contributor to septic injury-induced renal dysfunction is renal vascular dysfunction. Protein palmitoylation serves as a novel regulator of vascular function. Here, we examined whether palmitoyl acyltransferase (PAT)-DHHC21 contributes to septic injury-induced renal dysfunction through regulating renal hemodynamics. Multispectral optoacoustic imaging showed that cecal ligation and puncture (CLP)-induced septic injury caused impaired renal excretion, which was improved in DHHC21 functional deficient (Zdhhc21dep/dep) mice. DHHC21 deficiency attenuated CLP-induced renal pathology, characterized by tissue structural damage and circulating injury markers. Importantly, DHHC21 loss-of-function led to better-preserved renal perfusion and oxygen saturation after CLP. The CLP-caused reduction in renal blood flow was also ameliorated in Zdhhc21dep/dep mice. Next, CLP promoted the palmitoylation of vascular α1-adrenergic receptor (α1AR) and the activation of its downstream effector ERK, which were blunted in Zdhhc21dep/dep mice. Vasoreactivity analysis revealed that renal arteries from Zdhhc21dep/dep mice displayed reduced constriction response to α1AR agonist phenylephrine compared to those from wild-type mice. Consistently, inhibiting PATs with 2-bromopalmitate caused a blunted vasoconstriction response to phenylephrine in small arteries isolated from human kidneys. Therefore, DHHC21 contributes to impaired renal perfusion and function during septic injury via promoting α1AR palmitoylation-associated vasoconstriction.
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影响因子：
3.1
作者：
Marshall, Milton V.;Draney, Daniel;Sevick-Muraca, Eva M.;Olive, D. Michael
通讯作者：
Olive, D. Michael
DOI：
10.1186/cc12818
发表时间：
2013-07-12
期刊：
Critical care (London, England)
影响因子：
--
作者：
Burban M;Hamel JF;Tabka M;de La Bourdonnaye MR;Duveau A;Mercat A;Calès P;Asfar P;Lerolle N
通讯作者：
Lerolle N
影响因子：
4.8
作者：
Lobo, S;Greentree, WK;Deschenes, RJ
通讯作者：
Deschenes, RJ
影响因子：
4.8
作者：
Li, Yi;Martin, Brent R.;Hofmann, Sandra L.
通讯作者：
Hofmann, Sandra L.
影响因子：
9.6
作者：
Di Giantomasso, D;May, CN;Bellomo, R
通讯作者：
Bellomo, R