Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Goldyn Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Kidney Int. 2018 Aug;94(2):315-325. doi: 10.1016/j.kint.2018.02.026. Epub 2018 May 31.
The high serum fibroblast growth factor 23 (FGF23) levels in patients with acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with increased morbidity and mortality. Mice with folic acid-induced AKI had an increase in bone FGF23 mRNA expression together with an increase in serum FGF23 and several circulating cytokines including interleukin-6 (IL-6). Dexamethasone partially prevented the increase in IL-6 and FGF23 in the AKI mice. IL-6 knock-out mice fed an adenine diet to induce CKD failed to increase bone FGF23 mRNA and had a muted increase in serum FGF23 levels, compared with the increases in wild-type mice with CKD. Therefore, IL-6 contributes to the increase in FGF23 observed in CKD. Hydrodynamic tail injection of IL-6/soluble IL-6 receptor (sIL-6R) fusion protein hyper IL-6 (HIL-6) plasmid increased serum FGF23 levels. Circulating sIL-6R levels were increased in both CKD and AKI mice, suggesting that IL-6 increases FGF23 through sIL-6R-mediated trans-signaling. Renal IL-6 mRNA expression was increased in mice with either AKI or CKD, suggesting the kidney is the source for the increased serum IL-6 levels in the uremic state. HIL-6 also increased FGF23 mRNA in calvaria organ cultures and osteoblast-like UMR106 cells in culture, demonstrating a direct effect of IL-6 on FGF23 expression. HIL-6 increased FGF23 promoter activity through STAT3 phosphorylation and its evolutionarily conserved element in the FGF23 promoter. Thus, IL-6 increases FGF23 transcription and contributes to the high levels of serum FGF23 in both acute and chronic kidney disease.
血清成纤维细胞生长因子 23（FGF23）水平升高与急性肾损伤（AKI）和慢性肾脏病（CKD）患者的发病率和死亡率增加有关。叶酸诱导的 AKI 小鼠骨 FGF23mRNA 表达增加，同时血清 FGF23 和几种循环细胞因子（包括白细胞介素-6（IL-6））增加。地塞米松部分预防了 AKI 小鼠中 IL-6 和 FGF23 的增加。用腺嘌呤饮食诱导 CKD 的 IL-6 敲除小鼠未能增加骨 FGF23mRNA，并且与 CKD 野生型小鼠相比，血清 FGF23 水平增加幅度较小。因此，IL-6 导致 CKD 中观察到的 FGF23 增加。IL-6/可溶性 IL-6 受体（sIL-6R）融合蛋白的流体动力学尾部注射高 IL-6（HIL-6）质粒增加了血清 FGF23 水平。CKD 和 AKI 小鼠的循环 sIL-6R 水平均升高，表明 IL-6 通过 sIL-6R 介导的反信号增加 FGF23。AKI 或 CKD 小鼠的肾脏 IL-6mRNA 表达增加，提示肾脏是尿毒症状态下血清 IL-6 水平升高的来源。HIL-6 还增加了颅骨器官培养物和培养的成骨样 UMR106 细胞中的 FGF23mRNA，证明了 IL-6 对 FGF23 表达的直接作用。HIL-6 通过 STAT3 磷酸化及其在 FGF23 启动子中的进化保守元件增加 FGF23 启动子活性。因此，IL-6 增加了 FGF23 的转录，并导致急性和慢性肾脏病中血清 FGF23 水平升高。
