Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)

Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in pediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with glucocorticoids (GCs) reduces bone growth and BMD. The mechanisms causing GC-induced growth impairment have not been fully clarified. Fibroblast growth factor 23 (FGF23) is a peptide hormone that regulates phosphate homeostasis and bone growth. In pathological conditions, FGF23 excess or abnormal FGF receptors (FGFR) activity leads to bone growth impairment. Experimental data indicate that FGF23 expression is induced by chronic GC exposure. Therefore, we hypothesize that GCs impair bone growth by increasing FGF23 expression, which has direct effects on bone growth plate. In a post hoc analysis of a multicentric randomized clinical trial of prepubertal RTx children treated with early GC withdrawal or chronic GC treatment, we observed that GC withdrawal was associated with improvement in longitudinal growth and BMD, and lower plasma FGF23 levels as compared with a chronic GC group. In prepubertal rats, GC-induced bone growth retardation correlated with increased plasma FGF23 and bone FGF23 expression. Additionally, GC treatment decreased FGFR1 expression whereas it increased FGFR3 expression in mouse tibia explants. The GC-induced bone growth impairment in tibiae explants was prevented by blockade of FGF23 receptors using either a pan-FGFR antagonist (PD173074), a C-terminal FGF23 peptide (FGF23180-205) which blocks the binding of FGF23 to the FGFR-Klotho complex or a specific FGFR3 antagonist (P3). Finally, local administration of PD173074 into the tibia growth plate ameliorated cartilage growth impairment in GC-treated rats. These results show that GC treatment partially reduces longitudinal bone growth via upregulation of FGF23 and FGFR3 expression, thus suggesting that the FGF23/Klotho/FGFR3 axis at the growth plate could be a potential therapeutic target for the management of GC-induced growth impairment in children.Intact plasma FGF23 levels were measured before RTx, and 1 week and 1 year after RTx ( Fig. 2A). Both groups had > 95% decrease in plasma FGF23 1 week after RTx, compared with baseline values, without differences between both groups. One year after RTx, SC patients had 3.2-fold higher plasma FGF23 levels compared with SW patients (1 year SC: 32.2 [24.0 to 45.7] pg/mL; 1 year SW: 10.1 [5.4 to 14.2] pg/mL; p < 0.001). When these FGF23 plasma levels were compared with a control group of healthy children ( Supplemental Table 3), SC patients had increased concentrations, but no significant differences compared with the ◼ 2 DELUCCHI ET AL. Fig. 4. Dexamethasone reduced growth of rat metatarsal explants, via fibroblast growth factor receptors (FGFRs). Prenatal rat metatarsal explants (extracted on E20) were cultured in the presence of dexamethasone (Dex; 1 nM); RU486 (RU; 25 μM), a glucocorticoid receptor antagonist; PD173074 (PD; 100 nM), a pan-FGFR antagonist; recombinant FGF23 (444 pM); or cell culture alone (Control), over ...

Fibroblast growth factor 23 (FGF23) is mainly produced in the bone and, upon secretion, forms a complex with a FGF receptor and coreceptor αKlotho. FGF23 can exert several endocrine functions, such as inhibiting renal phosphate reabsorption and 1,25‐dihydroxyvitamin D3 production. Moreover, it has paracrine activities on several cell types, including neutrophils and hepatocytes. Klotho and Fgf23 deficiencies result in pathologies otherwise encountered in age‐associated diseases, mainly as a result of hyperphosphataemia‐dependent calcification. FGF23 levels are also perturbed in the plasma of patients with several disorders, including kidney or cardiovascular diseases. Here, we review mechanisms controlling FGF23 production and discuss how FGF23 regulation is perturbed in disease.

Hypertension (HTN) and chronic kidney disease (CKD) are increasingly recognized in pediatric patients and represent risk factors for cardiovascular morbidity and mortality later in life. In CKD, enhanced tubular sodium reabsorption is a leading cause of HTN due to augmented extracellular fluid volume expansion. The renin-angiotensin-aldosterone system (RAAS) upregulates various tubular sodium cotransporters that are also targets of the hormone fibroblast growth factor 23 (FGF23) and its co-receptor Klotho. FGF23 inhibits the activation of 1,25-dihydroxyvitamin D that is a potent suppressor of renin biosynthesis. Here we review the complex interactions and disturbances of the FGF23-Klotho axis, vitamin D, and the RAAS relevant to blood pressure regulation and discuss the therapeutic strategies aimed at mitigating their pathophysiologic contributions to HTN.