IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4
IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4
复制标题
IRF1 介导的 PGC1 α 下调导致 4 型心肾综合征
DOI：
10.1038/s41467-020-18519-0
复制
发表时间：
2020-09-16
影响因子：
16.6
通讯作者：
Zhao, Jinghong
中科院分区：
文献类型：
--
作者：
Huang, Yinghui;Wang, Shaobo;Zhao, Jinghong
心肾综合征4型(CRS4)是慢性肾脏病(CKD)的常见并发症，但其发病机制尚不清楚。在此，我们观察到CKD小鼠心肌线粒体的形态和功能的变化，尤其是氧化磷酸化和脂肪酸代谢的降低。高磷酸盐(HP)是CKD的一个标志，它通过下调过氧化体增殖物激活受体γ辅活化子1α(PGC1α)而导致心肌能量代谢功能障碍。此外，转录因子干扰素调节因子1(IRF1)是幽门螺杆菌通过组蛋白H3K9乙酰化上调的关键分子，通过直接与其启动子区域结合，导致幽门螺杆菌介导的PGC1α转录抑制。相反，在体外和体内，恢复PGC1α的表达或基因敲除IRF1显著减弱Hp诱导的变化。这些结果表明IRF1-PGC1α轴介导的心肌能量代谢重构在CRS4的发病机制中起着关键作用。心肾综合征4型(CRS4)的发病机制尚不清楚。在这里，作者确认IRF1-PGC1α轴介导的心肌能量代谢重构是CRS4发病机制的一个贡献因素，从而为减少CKD患者的心血管事件提供了潜在的新靶点。
Cardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1 alpha). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1 alpha by directly binding to its promoter region. Conversely, restoration of PGC1 alpha expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1 alpha axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4. The pathogenic mechanisms of cardiorenal syndrome type 4 (CRS4) remain unclear. Here, the authors identify IRF1-PGC1 alpha axis-mediated myocardial energy metabolism remodeling as a contributor to CRS4 pathogenesis, thus providing potential new targets for reducing cardiovascular events in CKD patients.