Fibroblast Growth Factor 23 Is Upregulated In The Kidney In A Chronic Kidney Disease Rat Model

The hormone fibroblast growth factor 23 (FGF23) is secreted from bone and is involved in phosphorus (P) metabolism. FGF23 mainly binds the FGF receptor, which interacts with aKlotho in the kidney or parathyroid and regulates Na-dependent phosphate co-transporter type Ila (NaPi-lla) and typellc (NaPi-11c) expression, 1,25-dihydroxyvitamin D-3 (1,25 (OH)(2)D-3) activity, and parathyroid hormone (PTH) secretion. In this study, we utilized heminephrectomized rats fed a high-P diet (HP Nx), rats subjected to a partial nephrectomy (PN) and rats with doxorubicin-induced renal failure (DXR) as chronic kidney disease (CKD) animal models and analyzed the P metabolism and FGF23 expression in the kidneys in each CKD model. We cultured HK2 cells with a high level of P, 1,25(OH)(2)D-3 or transforming growth factor-beta 1 (TG9 beta 1) to investigate the FGF23 expression mechanism. In both the HP Nx and PN rats, the blood FGF23 and PTH levels were increased. However, the 1,25 (OH)(2)D-3 level was increased in the HP Nx rats and decreased in the PN rats. In all three animal models, the mRNA expression of aklotho, NaPi-lla and NaPi-lIc was decreased, and the mRNA expression of TGF,61, collagen 1a1, osteopontin and FGF23 was elevated in the kidney. FGF23 protein and mRNA were expressed at high levels in the extended tubule epithelium, which was an osteopontin-positive region in the HP and PN rats. FGF23 and osteopontin mRNAs were expressed in HK2 cells incubated with TGF beta 1; however, these levels were not altered in HK2 cells incubated with 1,25(OH)(2)D-3 and high P levels in vitro. Altogether, FGF23 is expressed in the kidneys in CKD model rats. Following stimulation with TGF beta 1, the injured renal tubular epithelial cells are strongly suspected to express both FGF23 and osteopontin. FGF23 produced in the kidney might contribute to P metabolism in subjects with CKD.