Radhakrishnan Kamalakannan, Kim Yong-Hoon, Jung Yoon Seok, Kim Don-Kyu, Na Soon-Young, Lim Daejin, Kim Dong Hun, Kim Jina, Kim Hyung-Seok, Choy Hyon E, Cho Sung Jin, Lee In-Kyu, Ayvaz Şamil, Nittka Stefanie, Fliser Danilo, Schunk Stefan J, Speer Thimoteus, Dooley Steven, Lee Chul-Ho, Choi Hueng-Sik
School of Biological Sciences and Technology, Chonnam National University, 61186 Gwangju, Republic of Korea.
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 34141 Daejeon, Republic of Korea.
Proc Natl Acad Sci U S A. 2021 Apr 20;118(16). doi: 10.1073/pnas.2022841118.
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 ( < 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.
成纤维细胞生长因子23（FGF23）是一种通常源自骨骼的激素，在磷酸盐和维生素D稳态中起重要作用。在急性肾损伤（AKI）患者中，循环中FGF23水平升高与疾病进展和死亡率相关。然而，AKI中FGF23产生的器官和细胞类型以及其过度产生的分子机制仍未明确。为了深入了解，我们研究了叶酸（FA）诱导的小鼠急性肾损伤。有趣的是，与FGF23同时，在FA处理的小鼠肝脏中孤儿核受体ERR-γ的表达增加，并且ERR-γ的异位过表达足以诱导肝脏FGF23的产生。在患者和小鼠中，AKI伴随着全身IL-6的上调，IL-6先前被确定为肝脏中ERR-γ表达的上游调节因子。向FA处理的小鼠施用IL-6中和抗体或向健康小鼠施用重组IL-6证实IL-6是肝脏ERR-γ介导的FGF23产生的上游调节因子。还发现接受心脏手术的患者中高IL-6和FGF23水平之间存在显著（<0.001）的相互关联，可作为AKI的预测指标，这表明该发现具有临床相关性。最后，ERR-γ的肝脏特异性缺失或用ERR-γ反向激动剂治疗可降低FA诱导的AKI小鼠的肝脏FGF23表达和血浆FGF23水平。因此，ERR-γ反向激动剂可能代表一种降低AKI患者血浆FGF23不良水平的治疗策略。
