Direct, acute effects of Klotho and FGF23 on vascular smooth muscle and endothelium.
Chronic kidney disease (CKD) is regarded as a state of Klotho deficiency and FGF23 excess. In patients with CKD a strong association has been found between increased serum FGF23 and mortality risk, possibly via enhanced atherosclerosis, vascular stiffness, and vascular calcification. The aim of this study was to examine the hypothesis that soluble Klotho and FGF23 exert direct, rapid effects on the vessel wall. We used three in vitro models: mouse aorta rings, human umbilical vein endothelial cells, and human vascular smooth muscle cells (HVSMC). Increasing medium concentrations of soluble Klotho and FGF23 both stimulated aorta contractions and increased ROS production in HVSMC. Klotho partially reverted FGF23 induced vasoconstriction, induced relaxation on phosphate preconstricted aorta and enhanced endothelial NO production in HUVEC. Thus Klotho increased both ROS production in HVSMC and NO production in endothelium. FGF23 induced contraction in phosphate preconstricted vessels and increased ROS production. Phosphate, Klotho and FGF23 together induced no change in vascular tone despite increased ROS production. Moreover, the three compounds combined inhibited relaxation despite increased NO production, probably owing to the concomitant increase in ROS production. In conclusion, although phosphate, soluble Klotho and FGF23 separately stimulate aorta contraction, Klotho mitigates the effects of phosphate and FGF23 on contractility via increased NO production, thereby protecting the vessel to some extent against potentially noxious effects of high phosphate or FGF23 concentrations. This novel observation is in line with the theory that Klotho deficiency is deleterious whereas Klotho sufficiency is protective against the negative effects of phosphate and FGF23 which are additive.
INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
Isabelle
I
Six
INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
Hirokazu
H
Okazaki
INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
Priscilla
P
Gross
INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
Joanna
J
Cagnard
INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
Cédric
C
Boudot
INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France; Amiens University Medical Center, Amiens, France.
Julien
J
Maizel
INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
Tilman B
TB
Drueke
INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France; Amiens University Medical Center, Amiens, France.
Ziad A
ZA
Massy
D000818:Animals; D001011:Aorta / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000528:radiation effects; D014664:Vasodilation / Q000502:physiology
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D009589:Nitrogen Oxides; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins