FGF23, Klotho, and Vascular Calcification

Klotho and FGF23 interact with one another in a number of mechanisms that might explain the effects of klotho on longevity in mice: more klotho slows aging, while loss of klotho accelerates it. Vascular function is fairly high on that list, given the importance of the cardiovascular system in aging. The mechanism of interest in the research here is calcification of blood vessels, the dysfunction in cell populations in blood vessel walls that leads to mineralization akin to that involved in generation of bone tissue. Some of this is clearly the result of rising levels of cellular senescence and the harmful signaling that is produced by senescent cells. Investigations of the sort noted here are more concerned with proximate causes, however, in the sense of altered levels and interactions of various proteins.

Vascular calcification (VC) constitutes a major risk factor for cardiovascular (CV) morbidity and mortality and involves a complex regulated process of biomineralization that resembles osteogenesis. This process is mainly driven by the vascular smooth muscle cells (VSMCs), and includes the transformation of these cells into an osteoblastic phenotype.

Chronic kidney disease (CKD) is a major risk factor for CV disease (CVD) and is a clinical scenario closely related to the development of VC. In addition to the traditional CV risk factors, subjects with CKD are also exposed to other non-traditional factors predisposing for this pathology. Fibroblast growth factor (FGF) 23 is the most potent phosphatonin. This is an osteocyte-derived hormone produced in response to phosphate levels which, in combination with its cofactor Klotho, reduces the reabsorption of phosphate and the synthesis of active vitamin D in the kidneys. In patients with CKD, FGF23 concentrations increase with declining renal function and reach extremely high levels in end-stage renal disease. Clinical epidemiological studies have shown that FGF23 strongly predicts mortality in patients with CKD independently of other risk factors. These results suggest that FGF23 may causally be related to the high mortality observed in CKD patients and, importantly, that may exert direct effects on CV system besides its function as a phosphaturic hormone.

FGF23 binds to its cognate receptors (FGFRs), which are activated in the presence of the co-receptor Klotho. Our group and others described the expression of FGFR and Klotho in the human vascular wall, allowing to speculate that vascular tissue may be an objective for the actions of FGF23. Moreover, the synthesis of FGF23 by calcified vascular tissues and its contribution to CVD is an intriguing question not adequately studied. Only two previous works have explored the expression of FGF23 in calcified tissues, although solely coronary arteries and carotid atheroma plaques were analyzed. Moreover, the relationships of vascular FGF23 gene and protein expression levels with soluble FGF23 concentration and with the expression of Klotho and FGFRs in the vessels have not been previously established.

In this work, we determined the levels of both intact and fragmentary circulating FGF23 in 133 patients with established cardiovascular disease, the expression of FGF23, its receptors, and its co-receptor Klotho in vascular fragments of aorta, carotid, and femoral in 43 out of this group of patients, and in a control group of 20 organ donors. Patients with atherosclerosis and vascular calcification presented increased levels of FGF23 respect to the control group. Vascular immunoreactivity for FGF23 was also significantly increased in patients with vascular calcification as compared to patients without calcification and to controls. Finally, gene expression of FGF23 and RUNX2 were also higher and directly related in vascular samples with calcification. Conversely, expression of Klotho was reduced in patients with cardiovascular disease when comparing to controls. In conclusion, our findings link the calcification of the vascular tissue with the expression of FGF23 in the vessels and with the elevation of circulating levels this hormone.

Link: https://doi.org/10.18632/aging.102297


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