Blocking Sphingosine 1‐phosphate Metabolism With Fingolimod Prevents the Progression of Vascular Smooth Muscle Cells Calcification in Chronic Kidney Disease

Patients with chronic kidney disease, and particularly those under hemodialysis, are prone to develop cardiovascular complications, mostly due to the exacerbation of vascular calcification. Vascular calcification relies on the transdifferentiation of vascular smooth muscle cells into calcifying cells. Sphingosine 1-phosphate is a pleiotropic sphingolipid and an important regulator of osteogenesis and the cardiovascular system. Therefore, we explored the role of sphingosine 1-phosphate metabolism in chronic kidney disease-derived vascular calcification. Vascular calcification progression in chronic kidney disease and sphingosine 1-phosphate signaling were examined in calcified vascular smooth muscle cells, in aortic explants, in rats with adenine-induced chronic kidney disease, as well as in serum from hemodialysis patients. Sphingosine kinase 2 activity and sphingosine 1-phosphate secretion, under the control of phospholipase D1, were exacerbated in calcified vascular smooth muscle cells. Furthermore, phospholipase D1 knockout mice display significantly less circulating sphingosine 1-phosphate, supporting intertwined signalization cascades. Overall, sphingosine kinase expression and activity were upregulated in calcified aortic explants and in calcified aortas from rats. Sphingosine 1-phosphate was increased in the serum of rats with mild vascular calcification. The Food and Drug Administration-approved immunosuppressant drug fingolimod, a general modulator of S1P metabolism, strongly inhibited calcification in vascular smooth muscle cells and aortic explants. Additionally, fingolimod significantly reduced inflammation, attenuated metabolic syndrome and moderately inhibited aortic calcification in rats. Finally, we demonstrated for the first time that serum sphingosine 1-phosphate was significantly increased in hemodialysis patients with mild abdominal aortic calcification. Our findings open an unexplored therapeutic option, which is targeting sphingosine 1-phosphate metabolism, eventually with fingolimod, for the prevention and treatment of vascular calcification in chronic kidney disease patients.