David Valentin, Martin Aline, Isakova Tamara, Spaulding Christina, Qi Lixin, Ramirez Veronica, Zumbrennen-Bullough Kimberly B, Sun Chia Chi, Lin Herbert Y, Babitt Jodie L, Wolf Myles
Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Kidney Int. 2016 Jan;89(1):135-46. doi: 10.1038/ki.2015.290. Epub 2016 Jan 4.
Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with chronic kidney disease (CKD), but the mechanisms are poorly understood. Here we tested whether inflammation and iron deficiency regulate FGF23. In wild-type mice, acute inflammation induced by single injections of heat-killed Brucella abortus or interleukin-1β (IL-1β) decreased serum iron within 6 h, and was accompanied by significant increases in osseous Fgf23 mRNA expression and serum levels of C-terminal FGF23, but no changes in intact FGF23. Chronic inflammation induced by repeated bacteria or IL-1β injections decreased serum iron, increased osseous Fgf23 mRNA, and serum C-terminal FGF23, but modestly increased biologically active, intact FGF23 serum levels. Chronic iron deficiency mimicked chronic inflammation. Increased osseous FGF23 cleavage rather than a prolonged half-life of C-terminal FGF23 fragments accounted for the elevated C-terminal FGF23 but near-normal intact FGF23 levels in inflammation. IL-1β injection increased Fgf23 mRNA and C-terminal FGF23 levels similarly in wildtype and Col4a3(ko) mice with CKD but markedly increased intact FGF23 levels only in the CKD mice. Inflammation increased Fgf23 transcription by activating Hif1α signaling. Thus, inflammation and iron deficiency stimulate FGF23 production. Simultaneous upregulation of FGF23 cleavage in osteocytes maintains near-normal levels of biologically active, intact circulating FGF23, whereas downregulated or impaired FGF23 cleavage may contribute to elevated intact serum FGF23 in CKD.
慢性肾脏病（CKD）患者体内成纤维细胞生长因子23（FGF23）的循环水平升高，但其机制尚不清楚。在此，我们测试了炎症和缺铁是否调节FGF23。在野生型小鼠中，单次注射热灭活布鲁氏菌或白细胞介素-1β（IL-1β）诱导的急性炎症在6小时内降低血清铁，并伴有骨Fgf23 mRNA表达和血清C末端FGF23水平显著升高，但完整FGF23无变化。重复注射细菌或IL-1β诱导的慢性炎症降低血清铁，增加骨Fgf23 mRNA和血清C末端FGF23，但适度增加生物活性完整FGF23血清水平。慢性缺铁模拟慢性炎症。骨FGF23裂解增加而非C末端FGF23片段半衰期延长导致炎症时C末端FGF23升高但完整FGF23水平接近正常。IL-1β注射在野生型和患有CKD的Col4a3（ko）小鼠中同样增加Fgf23 mRNA和C末端FGF23水平，但仅在CKD小鼠中显著增加完整FGF23水平。炎症通过激活Hif-α信号增加Fgf23转录。因此，炎症和缺铁刺激FGF23产生。骨细胞中FGF23裂解的同时上调维持生物活性完整循环FGF23的接近正常水平，而FGF23裂解下调或受损可能导致CKD患者血清完整FGF23升高。
