Fibroblast growth factor 23 is induced by an activated renin–angiotensin–aldosterone system in cardiac myocytes and promotes the pro-fibrotic crosstalk between cardiac myocytes and fibroblasts

Abstract

Our data demonstrate that activated RAAS induces FGF23 expression in cardiac myocytes and thereby stimulates a pro-fibrotic crosstalk between cardiac myocytes and fibroblasts, which may contribute to myocardial fibrosis in CKD.

The axis of local cardiac endogenous Klotho-TGF-β1-Wnt signaling mediates cardiac fibrosis in human

“…Leifheit-Nestler et al reported that Klotho deficiency is associated with cardiac fibrosis in humans [37]; while this study focused on soluble Klotho, we show for the first time that local endogenous Klotho deficiency in human heart leads to cardiac fibrosis; we further reveal that cardiac endogenous Klotho expression and the degree of cardiac fibrosis in CKD patients have inverse relation even after adjustment for age and hypertension, ex vivo (Fig. 2).…”

“…However, Ghosh et al showed that the C57BL/6 mouse heart does express Klotho [34]; In studies using human heart samples, a previous group detected Klotho protein expression in the heart but didn't identify the separate specific cell types expressing Klotho [35]. In contrast, Leifheit-Nestler et al showed that there was no Klotho gene expression [36], but they did identify protein expression; theses authors suggested that the source of human heart Klotho is a soluble form from circulation [36,37].…”

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

“…Conversely, FGF23 induces left heart hypertrophy through FGFR4‐dependent NFAT signalling in a paracrine manner . The renin–angiotensin–aldosterone system activates FGF23 expression in cardiac myocytes .…”

“…Recently, a direct effect of angiotensin II and aldosterone on FGF23 expression in cardiac myocytes has been demonstrated, which may contribute to myocardial fibrosis in CKD .…”

Should We Consider the Cardiovascular System While Evaluating CKD-MBD?

“…It was shown that FGF23 stimulates the renin-angiotensin system by suppressing the expression of angiotensin-converting enzyme-2 (ACE2) in the kidney [98]. The study, which included both in vitro investigation of cardiac fibroblasts and myocytes and myocardial autopsy samples of patients with end-stage CKD, demonstrated that RAAS activation is responsible for the induction of FGF23 expression in cardiac myocytes and stimulation of pro-fibrotic crosstalk between cardiac myocytes and fibroblasts [99]. Besides, FGF23 also increases the production of transforming growth factor-β (TGF-β), lipocalin-2, and tumor necrosis factor-α (TNF-α), which are well known inflammatory markers [98].…”