High Fibroblast Growth Factor 23 concentrations in experimental renal failure impair calcium handling in cardiomyocytes

Abstract

The overwhelming majority of patients with chronic kidney disease (CKD) die prematurely before reaching end‐stage renal disease, mainly due to cardiovascular causes, of which heart failure is the predominant clinical presentation. We hypothesized that CKD‐induced increases of plasma FGF23 impair cardiac diastolic and systolic function. To test this, mice were subjected to 5/6 nephrectomy (5/6Nx) or were injected with FGF23 for seven consecutive days. Six weeks after surgery, plasma FGF23 was higher in 5/6Nx mice compared to sham mice (720 ± 31 vs. 256 ± 3 pg/mL, respectively, P = 0.034). In cardiomyocytes isolated from both 5/6Nx and FGF23 injected animals the rise of cytosolic calcium during systole was slowed (−13% and −19%, respectively) as was the decay of cytosolic calcium during diastole (−15% and −21%, respectively) compared to controls. Furthermore, both groups had similarly decreased peak cytosolic calcium content during systole. Despite lower cytosolic calcium contents in CKD or FGF23 pretreated animals, no changes were observed in contractile parameters of cardiomyocytes between the groups. Expression of calcium handling proteins and cardiac troponin I phosphorylation were similar between groups. Blood pressure, the heart weight:tibia length ratio, α‐MHC/β‐MHC ratio and ANF mRNA expression, and systolic and diastolic function as measured by MRI did not differ between groups. In conclusion, the rapid, CKD‐induced rise in plasma FGF23 and the similar decrease in cardiomyocyte calcium transients in modeled kidney disease and following 1‐week treatment with FGF23 indicate that FGF23 partly mediates cardiomyocyte dysfunction in CKD.

Cardiotoxicity of Uremic Toxins: A Driver of Cardiorenal Syndrome

“…An increase in FGF23 levels have been consistently demonstrated in both experimental CKD models [ 62 , 64 , 65 ] and CKD patients [ 65 , 66 , 67 ].…”

“…In cardiomyocytes isolated from 5/6 nephrectomy mice with FGF23 injection, impaired calcium handling determined by delay in cytosolic calcium rise during systole and delay in the decay of cytosolic calcium during diastole was demonstrated, suggesting role of FGF23 in myocardial contractile dysfunction [ 64 ]. A combined in vitro, ex vivo and in vivo study showed that FGF23 increased intracellular Ca 2+ in isolated cardiomyocytes treated with FGF23 and increased contractility of mice cardiac muscle strips [ 90 ].…”

Fibroblast growth factor 23: are we ready to use it in clinical practice?

“…Subsequent studies identified FGFR4 as the klotho-independent receptor for FGF23 on cardiomyocytes [95]. Specific blockade of FGFR4 by an antibody inhibited hypertrophy in the isolated cardiac myocytes and mice lacking the FGFR4 did not develop LVH in response to FGF23 [96], establishing FGFR4 as the receptor involved in FGF23-induced LVH [97]. However, these findings are not consistently reported, as in a transgenic mouse model of CKD, with high serum phosphate and FGF23, no signs of pathological cardiac remodelling were found [98].…”

An expert update on novel therapeutic targets for hyperphosphatemia in chronic kidney disease: preclinical and clinical innovations

“…Physiologically, the roles of FGF- 23 [62]. In vitro and studies in animal models demonstrate that FGF-23 can exert a direct effect on the heart, by inducing left ventricular hypertrophy (LVH) [63] in addition to affecting calcium fluxes in cardiomyocytes [64,65], both effects are independent of the presence of phosphate. These findings support the idea that FGF-23 may participate in inducing consequences of phosphate toxicity, at least on the heart in the CKD setting [66].…”