FGF23 impairs peripheral microvascular function in renal failure.

BACKGROUND: Cardiovascular diseases account for approximately 50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23.

METHODS: Mice were subjected to partial nephrectomy (5/6Nx) or sham-surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections, and CKD mice received FGF23 blocking antibodies following 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice.

RESULTS: 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside (SNP) or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine (ADMA) concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice.

CONCLUSIONS: In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD.