A Land of Controversy: Fibroblast Growth Factor-23 and Uremic Cardiac Hypertrophy

Abstract

Cardiac hypertrophy is a common feature in patients with CKD. Recent studies revealed that two phosphate regulators, fibroblast growth factor-23 and α-Klotho, are highly involved in the pathophysiologic process of CKD-induced cardiac hypertrophy. With decreasing renal function, elevated fibroblast growth factor-23 and decreased α-Klotho may contribute to cardiac hypertrophy by targeting the heart directly or by inducing systemic changes, such as vascular injury, hemodynamic disorders, and inflammation. However, several studies have demonstrated that disturbances in the fibroblast growth factor-23/α-Klotho axis do not lead to cardiac hypertrophy. In this review, we describe the cardiac effects of the fibroblast growth factor-23/α-Klotho axis and summarize recent progress in this field. In addition, we present not only the main controversies in this field but also provide possible directions to resolve these disputes.

Keywords: fibroblast growth factor-23; uremic cardiac hypertrophy; α-Klotho.

Figure 1.

The maturation and disintegration of FGF-23. FGF-23 precursor contains 251 amino acids (aa) and can be divided into a signal sequence (24 aa), a FGFR binding domain (155 aa), and an α-Klotho binding domain (72 aa). After removal of the signal sequence, iFGF-23 is secreted into the blood or cleaved between aa 179 and 180 into inactive amino-terminal FGF-23 and active cFGF-23.

Figure 2.

The cardiac effects of elevated FGF-23 is significantly different in CKD and XLH. Increased FGF-23 is observed in both CKD and XLH. However, the increase in FGF-23 occurs secondary to hyperphosphatemia, whereas it is idiopathic and induces hypophosphatemia in XLH. Elevated FGF-23 induces cardiac hypertrophy in CKD, whereas no cardiac changes are observed in XLH. In CKD, perhaps the relative levels of circulating FGF-23 and phosphate determine the prohypertrophic effects of FGF-23. Moreover, it is unclear whether any other factors might affect the prohypertrophic effect of FGF-23.

Figure 3.

FGF-23 activates MAPK signaling in the presence of sKlotho, whereas activates calcineurin signaling in the absence of sKlotho. (A) Under physiologic conditions, sKLOTHO functions as a coreceptor of FGF-23 and leads to MAPK signaling activation. Importantly, sKlotho only leads to a small increase in activation of MAPK activity in response to FGF-23, which means it may not induce robust activation of MAPK signaling and result in cardiac hypertrophy. (B) In CKD, decreased sKlotho blunts the interaction between FGF-23 and FGFR-1, and FGF-23 preferentially binds to FGFR-4, thus resulting in calcineurin cascade activation and pathologic cardiac hypertrophy.

Figure 4.

Direct and indirect effects of FGF-23 and KLOTHO on myocardium. In CKD, high FGF-23 level and Klotho/sKLOTHO deficiency lead to several changes in blood vessels, inflammatory responses, and the kidney, including vascular injury, inflammation, hypertension, and active 1,25-dihydroxyvitamin D₃ (1,25-[OH]₂-VitD₃) deficiency. These changes can induce cardiac hypertrophy directly and indirectly. Moreover, disturbances in FGF-23/sKLOTHO may induce cardiac hypertrophy and fibrosis directly. 25-OH-VitD₃, 25-hydroxyvitamin D₃; Cl⁻, chloride ion; Na⁺, sodium ion.