Directly Targeting HIF Activity Controls FGF23 Expression Revealing Translational Considerations for CKD-related Anemia
Julia Hum Ph.D
Medicine and Health Sciences
Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that regulates systemic phosphate homeostasis. In the common disorder chronic kidney disease (CKD), there is progressive anemia with concurrent elevation of FGF23 that continues to increase as kidney function declines. Our laboratory has found that FGF23 is markedly stimulated by anemia and hypoxia, and recently, by erythropoietin (EPO); however, the molecular mechanisms driving FGF23 in the context of CKD is not well understood. A new class of drugs, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI), stabilize HIFs to increase endogenous EPO production to correct anemia. Our goal was to test how FGF23 expression is controlled by HIF and its implications during CKD-related anemia. HIF-PH FG-4592 was tested in the setting of CKD mice. Mice were then treated for 3 weeks with 20 mg/kg FG-4592, equivalent to the human dose. Serum EPO levels significantly increased in FG-4592-treated casein control and adenine fed mice compared to vehicle controls. Intact FGF23 levels were significantly elevated in vehicle-treated adenine mice compared to casein controls, and these levels were further increased in adenine mice treated with FG-4592 (p<0.05). Further, FG-4592-treated adenine mice showed a significant recovery to near-normal ranges in red blood cell count, hemoglobin, and hematocrit after 3 weeks of treatment (p<0.01). We also tested kidney fibrosis via the markers Col1a1 and Col1a3, which were elevated in adenine mice compared to casein mice, and these levels were further increased in adenine mice treated with FG-4592. Additionally, inflammation markers including IL-6 were not significantly different across groups. These results suggest that PHD inhibitors can induce EPO in the failing kidney and do improve the anemia, however, constant Hif1a stabilization further elevates intact FGF23, potentially leading to detrimental downstream effects in patients with CKD.
Copyright 2018 all authors
Hum, Julia Ph.D; Wacker, Bryan OMS-1; and Marshall, Vince OMS-1, "Directly Targeting HIF Activity Controls FGF23 Expression Revealing Translational Considerations for CKD-related Anemia" (2018). MU-COM Research Day. 107.