Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy

Abstract

Summary Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cγ/calcineurin/nuclear factor of activated T cells signaling. A specific FGFR4 blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knock-in mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.

Cardiac hypertrophy in chronic kidney disease—role of Aldosterone and FGF23

“…In experimental models of mice, Faul et al [22] demonstrated that the FGF23-induced cardiac hypertrophy was abrogated by a phospholipase Cγ inhibitor (U73122) and a calcineurin inhibitor (cyclosporine A), but not by a MAP kinase inhibitor (PD98059), a PI3 kinase inhibitor (wartmannin), or an Akt inhibitor (A6730). Furthermore, pan FGF receptor blockade by PD173074 reduced LV mass and the cardiac expression of genes associated with LV hypertrophy [123], and the receptor involved was identified as FGF receptor 4 [124]. These findings lend support to the premise that FGF23-induced cardiac hypertrophy is mediated by the FGF receptor 4/PLCγ/calcineurin pathway.…”

Gold nanoparticle-based miR155 antagonist macrophage delivery restores the cardiac function in ovariectomized diabetic mouse model

“…41 The incubation time was 1 hour protected from light. After three washing steps, the sections were labeled by Hoechst diluted 1:1,000 in PBS.…”

Recent Advances in Fibro-blast Growth Factor-23 Functions

“…Thus disease states with α-Klotho deficiency may not involve global FGF-23 resistance, but rather they may in fact promote a switch of the FGF-23-induced signaling towards different cellular responses and outcomes in cells which express FGFRs, but not α-Klotho. 56 Previously FGF-23 functions on major organs, directly or indirectly, were considered only when α-Klotho was co-expressed along with FGFRs in the target tissue, 42 but with new studies that have been conducted exploring different mechanisms of action of FGF-23, researchers need to reassess the role FGF-23 plays in the organs and how that is achieved. There is clearly a delicate balance between FGF-23's α-Klotho dependent actions on the FGFRs and its α-Klotho independent actions on FGFR's throughout the body that need to be considered simultaneously and further studied.…”

“…56,65 Activation of this FGFR-4/calcineurin/NFAT pathway has been shown to be enough to cause cardiac hypertrophy in mice while FGFR-4 blockade, even with high serum FGF-23 levels, attenuates cardiac hypertrophy in rats with CKD. 56 In another study FGF-23 has been shown to induce cardiomyocyte hypertrophy via PLC-γ signaling, upstream of calcineurin/NFAT, independent of Klotho. 43 These studies bring to light questions regarding α-Klotho independent functions of FGF-23 in the heart that must be further investigated.…”