Blockade of myeloid differentiation protein 2 prevents obesity-induced inflammation and nephropathy.
Blockade of myeloid differentiation protein 2 prevents obesity-induced inflammation and nephropathy.
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阻断骨髓分化蛋白 2 可预防肥胖引起的炎症和肾病
DOI：
10.1111/jcmm.13287
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发表时间：
2017-12
影响因子：
5.3
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Fang Q;Wang L;Yang D;Chen X;Shan X;Zhang Y;Lum H;Wang J;Zhong P;Liang G;Wang Y
肥胖是肾脏疾病的一个主要和独立的危险因素。肥胖相关肾损伤的发病机制被认为至少涉及肾组织的富脂和促炎状态，但建立因果关系的具体机制尚不清楚。饱和脂肪酸在肥胖中升高，并已知会引起肾脏的慢性炎症。髓系分化蛋白2(MD2)是内毒素诱导的天然免疫反应和炎症反应中的重要蛋白。我们认为肥胖相关的肾损伤是由MD2调节的，从而推动了炎症性肾损伤。采用MD2基因敲除小鼠(KO)、野生型MD2基因敲除小鼠(HFD+L6H21)、MD2特异性抑制剂(MD2抑制剂)和软脂酸(PA)三种小鼠模型进行体内研究。分别在体外培养的肾小管上皮细胞、小鼠肾小球系膜细胞和原代巨噬细胞中进行研究。HFD小鼠表现为高脂血症、血清肌酐和蛋白尿增加。肾组织纤维化、炎性细胞因子、巨噬细胞浸润、核因子-κB和丝裂原活化增加。在KO小鼠或L6H21处理的小鼠中，没有观察到这种HFD诱导的肾脏损伤特征。给予PA的小鼠模拟HFD诱导的肾脏损伤，而MD2基因敲除可防止这种损伤。体外实验进一步证实MD2介导了PA诱导的炎症反应。MD2与肥胖相关的肾炎性损伤有因果关系。我们认为MD2是肥胖相关肾脏疾病未来治疗策略的一个有吸引力的靶点。
Obesity is a major and independent risk factor of kidney diseases. The pathogenic mechanisms of obesity‐associated renal injury are recognized to at least involve a lipid‐rich and pro‐inflammatory state of the renal tissues, but specific mechanisms establishing causal relation remain unknown. Saturated fatty acids are elevated in obesity, and known to induce chronic inflammation in kidneys. Myeloid differentiation protein 2 (MD2) is an important protein in lipopolysaccharide‐induced innate immunity response and inflammation. We suggested that obesity‐associated renal injury is regulated by MD2 thereby driving an inflammatory renal injury. The used three mouse models for in vivo study: MD2 knockout mice (KO) maintained on high fat diet (HFD), wild‐type mice on HFD plus L6H21, a specific MD2 inhibitor and KO mice given palmitic acid (PA) by IV injection. The in vitro studies were carried out in cultured renal tubular epithelial cells, mouse mesangial cells and primary macrophages, respectively. The HFD mice presented with increased hyperlipidemia, serum creatinine and proteinuria. Renal tissue from HFD mice had increased fibrosis, inflammatory cytokines, macrophage infiltration, and activation of NF‐κB and MAPKs. This HFD‐induced renal injury profile was not observed in KO mice or L6H21‐treated mice. Mice given PA mimmicked the HFD‐induced renal injury profiles, which were prevented by MD2 knockout. The in vitro data further confirmed MD2 mediates PA‐induced inflammation. MD2 is causally related with obesity‐associated renal inflammatory injury. We believe that MD2 is an attractive target for future therapeutic strategies in obesity‐associated kidney diseases.
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影响因子：
5.6
作者：
Redon, Josep;Lurbe, Empar
通讯作者：
Lurbe, Empar
DOI：
10.1073/pnas.1100255108
发表时间：
2011-09-13
影响因子：
11.1
作者：
Stienstra, Rinke;van Diepen, Janna A.;Kanneganti, Thirumala-Devi
通讯作者：
Kanneganti, Thirumala-Devi
影响因子：
16.6
作者：
Jia, Lin;Vianna, Claudia R.;Fukuda, Makoto;Berglund, Eric D.;Liu, Chen;Tao, Caroline;Sun, Kai;Liu, Tiemin;Harper, Matthew J.;Lee, Charlotte E.;Lee, Syann;Scherer, Philipp E.;Elmquist, Joel K.
通讯作者：
Elmquist, Joel K.
影响因子：
3.6
作者：
BOURGEOIS, F;ALEXIU, A;LEMONNIER, D
通讯作者：
LEMONNIER, D
影响因子：
1.7
作者：
Martinez-Morua, Antonia;Soto-Urquieta, Maria G.;Ramirez-Emiliano, Joel
通讯作者：
Ramirez-Emiliano, Joel