최흥식 (전남대학교)

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전남대학교

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Proc. Natl. Acad. Sci. USA, April 20, 2021, 118 (16) : e2022841118 | https://doi.org/10.1073/pnas.2022841118 Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury

Kamalakannan Radhakrishnan^a,1, Yong-Hoon Kim^b,c,1, Yoon Seok Jung^a, Don-Kyu Kim^d, Soon-Young Na^a, Daejin Lim^e, Dong Hun Kim^f, Jina Kim^g, Hyung-Seok Kim^h, Hyon E. Choy^e, Sung Jin Cho^g,i, In-Kyu Lee^i,j, Samil Ayvaz^k, Stefanie Nittka^l, Danilo Fliser^m, Stefan J. Schunk^m, Thimoteus Speer^m, Steven Dooley^k,2, Chul-Ho Lee^b,c,2, and Hueng-Sik Choi^a,2

^aSchool of Biological Sciences and Technology, Chonnam National University, 61186 Gwangju, Republic of Korea; ^bLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 34141 Daejeon, Republic of Korea; ^cDepartment of Functional Genomics, Korea Research Institute of Biosciences and Biotechnology School of Bioscience, University of Science and Technology, 34141 Daejeon, Republic of Korea; ^dDepartment of Molecular Biotechnology, Chonnam National University, 61186 Gwangju, Republic of Korea; ^eDepartment of Microbiology, Chonnam National University Medical School, 61468 Gwangju, Republic of Korea; ^fDepartment of Biomedical Science, Graduate School, Kyungpook National University, 41404 Daegu, Republic of Korea; ^gNew Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation, 41061 Daegu, Republic of Korea; ^hDepartment of Forensic Medicine, Chonnam National University Medical School, 61468 Gwangju, Republic of Korea; ⁱLeading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, 41404 Daegu, Republic of Korea; ^jDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 41944 Daegu, Republic of Korea; ^kDepartment of Medicine II, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; ^lInstitute for Clinical Chemistry, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; and ^mDepartment of Internal Medicine IV, Nephrology and Hypertension, Saarland University, D-66421
Homburg/Saar, German

¹K.R. and Y.-H.K. contributed equally to this work.
²To whom correspondence may be addressed.

Abstract

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.

acute kidney injury, ERR-γ, FGF23, interleukin 6, orphan nuclear receptor

논문정보

형식Research article
게재일2021년 04월 (BRIC 등록일 2021-04-26)
연구진국내(교신)+국외 연구진
분야 생명과학 > 수의학

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