Interleukin-6 blockade reduces salt-induced cardiac inflammation and fibrosis in subtotal nephrectomized mice.
Interleukin-6 blockade reduces salt-induced cardiac inflammation and fibrosis in subtotal nephrectomized mice.
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Interleukin-6 阻断可减少肾次全切除小鼠中盐诱导的心脏炎症和纤维化。
DOI：
10.1152/ajprenal.00396.2021
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Ito Y.
中科院分区：
文献类型：
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作者：
Tanaka H;Sun T;Kinashi H;Kamiya K;Yamaguchi M;Nobata H;Sakata F;Kim H;Mizuno M;Kunoki S;Sakai Y;Hirayama A;Soga T;Yoshikawa K;Ishimoto T;Ito Y.
心血管疾病是慢性肾脏病（CKD）患者最常见的合并症，影响其预后和生活质量。心脏纤维化在伴有左心室舒张功能不全的CKD患者中很常见，并且与心力衰竭和死亡率的风险增加相关。最近的证据表明，高盐摄入会激活与局部钠积累相关的免疫反应。我们报道了高盐摄入促进肾大部切除（Nx）小鼠的心脏炎症。我们研究了MR 16 -1（一种大鼠抗小鼠白细胞介素（IL）-6受体单克隆抗体）对盐负荷（Nx-盐）Nx小鼠的作用。与对照大鼠IgG 1（Nx-盐-大鼠IgG 1）处理的Nx-盐小鼠相比，MR 16 -1处理的Nx-盐小鼠（Nx-盐-MR 16 -1）心脏中单核细胞趋化蛋白-1、肿瘤坏死因子-α、IL-1β和IL-6 mRNA的表达以及巨噬细胞浸润显著降低。相应地，与Nx-盐-大鼠IgG 1小鼠相比，Nx-盐-MR 16 -1小鼠的心脏纤维化显著减弱。此外，在Nx盐-MR 16 -1小鼠的心脏中，与Nx盐-大鼠IgG 1小鼠相比，氧化应激标志物烟酰胺腺嘌呤二核苷酸磷酸氧化酶-2的mRNA表达显著下调。心脏代谢物的增加，包括组氨酸和γ-丁酰甜菜碱，也被IL-6阻断治疗逆转。总之，IL-6阻断剂在Nx盐小鼠心脏中发挥抗炎、抗纤维化和部分抗氧化作用。新&值得注意的是在本研究中，IL-6阻断剂在高盐饮食的CKD小鼠心脏中发挥抗炎、抗纤维化和部分抗氧化作用。因此，IL-6可能介导CKD患者高盐摄入诱导的心脏纤维化，这一发现具有治疗意义。值得注意的是，下一个治疗意义可能只是加强低盐饮食或利尿剂，并进一步研究这些措施的抗炎作用，而不是用高盐饮食阻断IL-6。
Cardiovascular disease is the most common comorbidity in patients with chronic kidney disease (CKD), affecting both their prognosis and quality of life. Cardiac fibrosis is common in patients with CKD with left ventricular diastolic dysfunction, and it is associated with increased risk of heart failure and mortality. Recent evidence suggests that high salt intake activates immune responses associated with local accumulation of sodium. We reported that high salt intake promotes cardiac inflammation in subtotal nephrectomized (Nx) mice. We investigated the effects of administration of MR16-1, a rat anti-mouse monoclonal interleukin (IL)-6 receptor antibody, in Nx mice with salt loading (Nx-salt). Expression of monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-1β, and IL-6 mRNAs and macrophage infiltration was significantly reduced in the heart of Nx-salt mice treated with MR16-1 (Nx-salt-MR16-1) compared with Nx-salt mice treated with control rat rat IgG1 (Nx-salt-rat IgG1). Correspondingly, cardiac fibrosis was significantly attenuated in Nx-salt-MR16-1 mice compared with Nx-salt-rat IgG1 mice. Furthermore, in the heart of Nx-salt-MR16-1 mice, expression of mRNA for nicotinamide adenine dinucleotide phosphate oxidase-2, an oxidative stress marker, was significantly downregulated compared with Nx-salt-rat IgG1 mice. Increases in cardiac metabolites, including histidine and γ-butyrobetaine, were also reversed by IL-6 blockade treatment. In conclusion, IL-6 blockade exerts anti-inflammatory, antifibrotic, and partial antioxidative effects in the heart of Nx-salt mice.NEW & NOTEWORTHYIn the present study, IL-6 blockade exerted anti-inflammatory, antifibrotic, and partial antioxidative effects on the hearts of mice with CKD on a high-salt diet. Therefore, IL-6 potentially mediates cardiac fibrosis induced by high salt intake in patients with CKD, a finding with therapeutic implications. Of note, the next therapeutic implication may simply be the reinforcement of low-salt diets or diuretics and further research on the anti-inflammatory effects of these measures rather than IL-6 blockade with high-salt diet.