IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4

Yinghui Huang, Shaobo Wang, Jie Zhou, Yong Liu, Changhong Du, Ke Yang, Xianjin Bi, Mingying Liu, Wenhao Han, Kailong Wang, Jiachuan Xiong, Song Wang, Yue Wang, Ling Nie, Chi Liu, Daohai Zhang, Jun Gu, Chunyu Zeng and Jinghong Zhao ()
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Yinghui Huang: Army Medical University (Third Military Medical University)
Shaobo Wang: Army Medical University (Third Military Medical University)
Jie Zhou: Army Medical University
Yong Liu: Army Medical University (Third Military Medical University)
Changhong Du: Army Medical University
Ke Yang: Army Medical University (Third Military Medical University)
Xianjin Bi: Army Medical University (Third Military Medical University)
Mingying Liu: Army Medical University (Third Military Medical University)
Wenhao Han: Army Medical University (Third Military Medical University)
Kailong Wang: Army Medical University (Third Military Medical University)
Jiachuan Xiong: Army Medical University (Third Military Medical University)
Song Wang: Army Medical University
Yue Wang: Army Medical University (Third Military Medical University)
Ling Nie: Army Medical University (Third Military Medical University)
Chi Liu: Army Medical University (Third Military Medical University)
Daohai Zhang: Army Medical University (Third Military Medical University)
Jun Gu: Peking University
Chunyu Zeng: Army Medical University
Jinghong Zhao: Army Medical University (Third Military Medical University)

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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 (PGC1α). 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 PGC1α by directly binding to its promoter region. Conversely, restoration of PGC1α expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4.

Date: 2020
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DOI: 10.1038/s41467-020-18519-0

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