Abstract
Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulation of profibrotic factors. We hypothesized that FGF23 may also stimulate the local renin–angiotensin–aldosterone system (RAAS) in the heart, thereby further promoting the progression of FGF23-mediated cardiac pathologies. We evaluated LVH and fibrosis in association with cardiac FGF23 and activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals followed by in vitro studies with isolated neonatal rat ventricular myocytes and fibroblast (NRVM, NRCF), respectively. Uremic rats showed enhanced cardiomyocyte size and cardiac fibrosis compared with sham. The cardiac expression of Fgf23 and RAAS genes were increased in 5/6Nx rats and correlated with the degree of cardiac fibrosis. In NRVM and NRCF, FGF23 stimulated the expression of RAAS genes and induced Ngal indicating mineralocorticoid receptor activation. The FGF23-mediated hypertrophic growth of NRVM and induction of NFAT target genes were attenuated by cyclosporine A, losartan and spironolactone. In NRCF, FGF23 induced Tgfb and Ctgf, which were suppressed by losartan and spironolactone, only. Our data suggest that FGF23-mediated activation of local RAAS in the heart promotes cardiac hypertrophy and fibrosis.
Highlights
Chronic kidney disease (CKD) is a global health issue [1] affecting over 850 million people worldwide according to the International Society of Nephrology (ISN)
Cardiac hypertrophy and fibrosis are common comorbidities in CKD patients [32] and it is well-established that fibroblast growth factor 23 (FGF23) directly promotes left ventricular hypertrophy (LVH) via calcineurin/nuclear factor of activated T cells (NFAT) signaling activation in uremia [9,33]
As published before [11], 5/6Nx rats showed increased heart weight to body weight ratio accompanied with enhanced cardiomyocyte size, enhanced mRNA expression of Fgf23 in heart and bone tissue and significantly decreased phosphorylation of NFAT suggesting FGF23-mediated activation of calcineurin/NFAT pathway due to uremia (Table 1)
Summary
Chronic kidney disease (CKD) is a global health issue [1] affecting over 850 million people worldwide according to the International Society of Nephrology (ISN). One of the major causes of death in this patient population are cardiovascular events [2,3], which are partially attributed to rising fibroblast growth factor 23 (FGF23) serum levels in CKD [4]. Clinical studies in CKD patients showed a correlation of elevated FGF23 levels to left ventricular hypertrophy (LVH) [6,7]. FGF23 is expressed by cardiomyocytes [10], and cardiac FGF23 expression is increased in uremic rats [11], transverse aortic constriction-operated mice [12] or mice after myocardial infarction [13] as well as in patients with CKD [14] and heart failure [15]
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