Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease.
Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease.
复制标题
G0/G1开关2的抑制可改善慢性肾脏疾病的肾脏炎症。
DOI：
10.1016/j.ebiom.2016.10.008
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发表时间：
2016-11
期刊：
影响因子：
11.1
通讯作者：
Ohdo S
中科院分区：
文献类型：
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作者：
Matsunaga N;Ikeda E;Kakimoto K;Watanabe M;Shindo N;Tsuruta A;Ikeyama H;Hamamura K;Higashi K;Yamashita T;Kondo H;Yoshida Y;Matsuda M;Ogino T;Tokushige K;Itcho K;Furuichi Y;Nakao T;Yasuda K;Doi A;Amamoto T;Aramaki H;Tsuda M;Inoue K;Ojida A;Koyanagi S;Ohdo S
慢性肾脏疾病（CKD）是一个全球健康问题，迫切需要治疗CKD的新型疗法。在这里，我们表明抑制G0/G1开关2（G0S2）可以缓解CKD小鼠模型中的肾脏炎症。在野生型5/6肾切除术（5/6nx）小鼠的肾脏中，趋化因子（C-C基序）配体2（CCL2）的肾脏表达增加了。此外，在编码昼夜节律运动输出周期Kaput（时钟）的基因中携带纯合突变的5/6NX clk/clk小鼠没有表现出凋亡或F4/80阳性细胞的诱导。 G0S2在野生型5/6NX小鼠中的肾脏表达对于通过p65对CCL2进行反式激活很重要。这些病理通过G0S2敲低改善。此外，通过高通量化学筛选确定了一种新型的G0S2表达的小分子抑制剂，抑制剂抑制了5/6NX小鼠的肾脏炎症。这些发现表明，G0S2抑制剂可能在CKD治疗中应用。
CKD中的慢性肾脏炎症通过时钟突变改善。
G0S2对于时钟突变的抗炎作用很重要。
G0S2的一种新型的小分子抑制剂改善了CKD中的肾脏炎症。
Matsunaga等。发现G0/G1开关2（G0S2）对于肾脏炎症很重要，并且一种新型的G0S2的小分子抑制剂改善了慢性肾脏疾病（CKD）的肾功能障碍。 G0S2增强了P65介导的转录。此外，肾脏炎症通过分子时钟机制受到G0S2/STAT5的调节。最后，G0S2敲低或抑制可改善CKD中的肾功能障碍。
Chronic kidney disease (CKD) is a global health problem, and novel therapies to treat CKD are urgently needed. Here, we show that inhibition of G0/G1 switch 2 (G0s2) ameliorates renal inflammation in a mouse model of CKD. Renal expression of chemokine (C-C motif) ligand 2 (Ccl2) was increased in response to p65 activation in the kidneys of wild-type 5/6 nephrectomy (5/6Nx) mice. Moreover, 5/6Nx Clk/Clk mice, which carry homozygous mutations in the gene encoding circadian locomotor output cycles kaput (CLOCK), did not exhibit aggravation of apoptosis or induction of F4/80-positive cells. The renal expression of G0s2 in wild-type 5/6Nx mice was important for the transactivation of Ccl2 by p65. These pathologies were ameliorated by G0s2 knockdown. Furthermore, a novel small-molecule inhibitor of G0s2 expression was identified by high-throughput chemical screening, and the inhibitor suppressed renal inflammation in 5/6Nx mice. These findings indicated that G0s2 inhibitors may have applications in the treatment of CKD. Chronic renal inflammation in CKD was ameliorated by clock mutation. G0s2 was important for the anti-inflammatory effects of clock mutation. A novel small-molecule inhibitor of G0s2 ameliorated renal inflammation in CKD. Matsunaga et al. found that G0/G1 switch 2 (G0s2) was important for renal inflammation and that a novel small-molecule inhibitor of G0s2 ameliorated renal dysfunction in chronic renal disease (CKD). G0s2 enhanced p65-mediated transcription. Moreover, renal inflammation was regulated by G0s2/Stat5 through the molecular clock mechanism. Finally, G0s2 knockdown or inhibition ameliorated renal dysfunction in CKD.