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Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury

Fibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are associated with disease progression and mortality. However, the organ and cell type of FGF23 produ...

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Main Authors: Radhakrishnan, Kamalakannan (Author) , Kim, Yong-Hoon (Author) , Jung, Yoon Seok (Author) , Kim, Don-Kyu (Author) , Na, Soon-Young (Author) , Lim, Daejin (Author) , Kim, Dong Hun (Author) , Kim, Jina (Author) , Kim, Hyung-Seok (Author) , Choy, Hyon E. (Author) , Cho, Sung Jin (Author) , Lee, In-Kyu (Author) , Ayvaz, Şamil (Author) , Nittka, Stefanie (Author) , Fliser, Danilo (Author) , Schunk, Stefan J. (Author) , Speer, Thimoteus (Author) , Dooley, Steven (Author) , Lee, Chul-Ho (Author) , Choi, Hueng-Sik (Author)
Format: Article (Journal)
Language:English
Published: April 20,2021
In: Proceedings of the National Academy of Sciences of the United States of America
Year: 2021, Volume: 118, Issue: 16, Pages: 1-11
ISSN:1091-6490
DOI:10.1073/pnas.2022841118
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1073/pnas.2022841118
Verlag, lizenzpflichtig, Volltext: https://www.pnas.org/content/118/16/e2022841118
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Author Notes:Kamalakannan Radhakrishnan, Yong-Hoon Kim, Yoon Seok Jung, Don-Kyu Kim, Soon-Young Na, Daejin Lim, Dong Hun Kim, Jina Kim, Hyung-Seok Kim, Hyon E. Choy, Sung Jin Cho, In-Kyu Lee, Şamil Ayvaz, Stefanie Nittka, Danilo Fliser, Stefan J. Schunk, Thimoteus Speer, Steven Dooley, Chul-Ho Lee, and Hueng-Sik Choi
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Summary:Fibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are associated with disease progression and mortality. However, the organ and cell type of FGF23 production in AKI and the molecular mechanism of its excessive production are still unidentified. For insight, we investigated folic acid (FA)-induced AKI in mice. Interestingly, simultaneous with FGF23, orphan nuclear receptor ERR-γ expression is increased in the liver of FA-treated mice, and ectopic overexpression of ERR-γ was sufficient to induce hepatic FGF23 production. In patients and in mice, AKI is accompanied by up-regulated systemic IL-6, which was previously identified as an upstream regulator of ERR-γ expression in the liver. Administration of IL-6 neutralizing antibody to FA-treated mice or of recombinant IL-6 to healthy mice confirms IL-6 as an upstream regulator of hepatic ERR-γ-mediated FGF23 production. A significant (P < 0.001) interconnection between high IL-6 and FGF23 levels as a predictor of AKI in patients that underwent cardiac surgery was also found, suggesting the clinical relevance of the finding. Finally, liver-specific depletion of ERR-γ or treatment with an inverse ERR-γ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in mice with FA-induced AKI. Thus, inverse agonist of ERR-γ may represent a therapeutic strategy to reduce adverse plasma FGF23 levels in AKI.
Item Description:Gesehen am 02.08.2021
Physical Description:Online Resource
ISSN:1091-6490
DOI:10.1073/pnas.2022841118

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