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.
References
[1]
Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH (2004) Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med 164: 659–663. doi: 10.1001/archinte.164.6.659
[2]
Stam F, van Guldener C, Becker A, Dekker JM, Heine RJ, et al. (2006) Endothelial dysfunction contributes to renal function-associated cardiovascular mortality in a population with mild renal insufficiency: the Hoorn study. J Am Soc Nephrol 17: 537–545. doi: 10.1681/asn.2005080834
[3]
Recio-Mayoral A, Banerjee D, Streather C, Kaski JC (2011) Endothelial dysfunction, inflammation and atherosclerosis in chronic kidney disease—a cross-sectional study of predialysis, dialysis and kidney-transplantation patients. Atherosclerosis 216: 446–451. doi: 10.1016/j.atherosclerosis.2011.02.017
[4]
Montezano AC, Touyz RM (2012) Reactive oxygen species and endothelial function—role of nitric oxide synthase uncoupling and Nox family nicotinamide adenine dinucleotide phosphate oxidases. Basic Clin Pharmacol Toxicol 110: 87–94. doi: 10.1111/j.1742-7843.2011.00785.x
[5]
Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, et al. (1998) Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 242: 626–630. doi: 10.1016/s0014-5793(98)00127-6
[6]
Prié D, Ure？a Torres P, Friedlander G (2009) Latest findings in phosphate homeostasis. Kidney Int 75: 882–889. doi: 10.1038/ki.2008.643
[7]
Lim K, Lu TS, Molostvov G, Lee C, Lam FT, et al. (2012) Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23. Circulation 125: 2243–2255. doi: 10.1161/circulationaha.111.053405
[8]
Quarles LD (2008) Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 118: 3820–3828. doi: 10.1172/jci36479
[9]
Nakai K, Komaba H, Fukagawa M (2010) New insights into the role of fibroblast growth factor 23 in chronic kidney disease. J Nephrol 23: 619–625.
[10]
Saito T, Fukumoto S (2009) Fibroblast Growth Factor 23 (FGF23) and Disorders of Phosphate Metabolism. Int J Pediatr Endocrinol 2009: 496514. doi: 10.1186/1687-9856-2009-496514
[11]
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, et al. (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390: 45–51.
[12]
Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, et al. (2004) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113: 561–568. doi: 10.1172/jci19081
[13]
Galitzer H, Ben-Dov IZ, Silver J, Naveh-Many T (2010) Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int 77: 211–218. doi: 10.1038/ki.2009.464
[14]
Canalejo R, Canalejo A, Martinez-Moreno JM, Rodriguez-Ortiz ME, Estepa JC, et al. (2010) FGF23 fails to inhibit uremic parathyroid glands. J Am Soc Nephrol 21: 1125–1135. doi: 10.1681/asn.2009040427
[15]
Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, et al. (2011) FGF23 induces left ventricular hypertrophy. J Clin Invest 121: 4393–4408. doi: 10.1172/jci46122
[16]
Mirza MA, Larsson A, Lind L, Larsson TE (2009) Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis 205: 385–390. doi: 10.1016/j.atherosclerosis.2009.01.001
[17]
Saito Y, Yamagishi T, Nakamura T, Ohyama Y, Aizawa H, et al. (1998) Klotho protein protects against endothelial dysfunction. Biochem Biophys Res Commun 248: 324–329. doi: 10.1006/bbrc.1998.8943
[18]
Saito Y, Nakamura T, Ohyama Y, Suzuki T, Iida A, et al. (2000) In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome. Biochem Biophys Res Commun 276: 767–772. doi: 10.1006/bbrc.2000.3470
[19]
Six I, Maizel J, Barreto FC, Rangrez AY, Dupont S, et al. (2012) Effects of phosphate on vascular function under normal conditions and influence of the uraemic state. Cardiovasc Res 96: 130–139. doi: 10.1093/cvr/cvs240
[20]
Rakugi H, Matsukawa N, Ishikawa K, Yang J, Imai M, et al. (2007) Anti-oxidative effect of Klotho on endothelial cells through cAMP activation. Endocrine 31(1): 82–87. doi: 10.1007/s12020-007-0016-9
[21]
Yang K, Nie L, Huang Y, Zhang J, Xiao T, et al. (2012) Amelioration of uremic toxin indoxyl sulfate-induced endothelial cell dysfunction by Klotho protein. Toxicol Lett 215: 77–83. doi: 10.1016/j.toxlet.2012.10.004
[22]
Carracedo J, Buendía P, Merino A, Madue？o JA, Peralbo E, et al. (2012) Klotho modulates the stress response in human senescent endothelial cells. Mech Ageing Dev 133: 647–654. doi: 10.1016/j.mad.2012.09.002
[23]
Nakamura T, Saito Y, Ohyama Y, Masuda H, Sumino H, et al. (2002) Production of nitric oxide, but not prostacyclin, is reduced in klotho mice. Jpn J Pharmacol 89: 149–156. doi: 10.1254/jjp.89.149
[24]
Izquierdo MC, Perez-Gomez MV, Sanchez-Ni？o MD, Sanz AB, Ruiz-Andres O, et al. (2012) Klotho, phosphate and inflammation/ageing in chronic kidney disease. Nephrol Dial Transplant 27 Suppl 4iv6–10. doi: 10.1093/ndt/gfs426
[25]
Hu MC, Shi M, Zhang J, Qui？ones H, Griffith C, et al. (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22: 124–136. doi: 10.1681/asn.2009121311
[26]
Nagano N, Miyata S, Abe M, Kobayashi N, Wakita S, et al. (2006) Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats. Kidney Int 69: 531–537. doi: 10.1038/sj.ki.5000020
[27]
Lindberg K, Olauson H, Amin R, Ponnusamy A, Goetz R, et al. (2013) Arterial Klotho Expression and FGF23 Effects on Vascular Calcification and Function. PLoS One 8(4): e60658. doi: 10.1371/journal.pone.0060658
[28]
Agarwal I, Ide N, Ix JH, Kestenbaum B, Lanske B, et al. (2014) Fibroblast growth factor-23 and cardiac structure and function. J Am Heart Assoc 3(1): e000584.
