PS-B02-3: FGF23 EXACERBATES CARDIAC FIBROSIS IN DOCA-SALT HYPERTENSIVE MICE THROUGH LOCALLY ABNORMAL VITAMIN D METABOLISM

Abstract

Backgrounds: Fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease (CKD), but the mechanisms underlying the effect of FGF23 on cardiac function remain to be investigated. Herein, we studied the effect of continuous intravenous (CIV) FGF23 loading in a deoxycorticosterone acetate (DOCA)-salt mouse model that has mild CKD and hypertension, and heart failure with a preserved ejection fraction (HFpEF). Design and method: Wild type male mice (n = 16) were allocated randomly to four groups: normal control (NC), vehicle-treated DOCA-salt mice (V), FGF23-treated DOCA-salt mice (F), and FGF23 and calcitriol-treated DOCA-salt mice (C). The DOCA-salt mice received agents by CIV for ten days via an infusion mini-pump, uninephrectomized, and cardiac changes were evaluated in these mice. Results: DOCA-salt mice that received FGF23 showed a marked increase in serum FGF23 (249 pg/mL in V, 1416 pg/mL in F, and 1261 pg/mL in C) than NC (51 pg/mL). Echocardiography in these DOCA-salt mice revealed HFpEF. These mice also showed exacerbation of myocardial fibrosis area (7.0% in V, 13.2% in F, and 3.8% in C) concomitant with an inverse and significant correlation with Cyp27b1 expression (r = -0.79, P < 0.01). Calcitriol treatment attenuated the FGF23-induced cardiac fibrosis (F vs. C, P < 0.01) and improved diastolic function (early-to-atrial wave ratio in doppler echocardiography, 0.7 in F vs. 2.0 in C; P < 0.01) via inhibition of transforming growth factor (TGF)-beta signaling. Protein expression levels of TGF-beta was significantly higher in F (1.32-fold to NC; P < 0.01) than in NC, and significantly lower in C (0.96-fold to NC; P < 0.05) than in F. This effect was independent of systemic and local FGF23 levels. Conclusions: These results suggest that CIV FGF23 loading induced cardiac fibrosis concomitantly with locally abnormal vitamin D metabolism, and this might have contributed to HFpEF progression in the DOCA-salt mice model. Thus, cardiac toxicity of FGF23 may be partly due to vitamin D inactivation in cardiac tissue. Calcitriol has cardioprotective effects by mediating TGF-beta signaling, independently of local and systemic FGF23 levels.