Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease. Vascular calcification (VC) in the medial layer of the vessel wall is a unique and prominent feature in patients with advanced chronic kidney disease and is now recognized as an important predictor and independent risk factor for cardiovascular and all-cause mortality in these patients. VC in chronic kidney disease is triggered by the transformation of vascular smooth muscle cells (VSMCs) into osteoblasts as a consequence of elevated circulating inorganic phosphate (P i ) levels, due to poor kidney function. The objective of our study was to investigate the role of TDAG51 (T-cell death-associated gene 51) in the development of medial VC.
Methods and Results:
Using primary mouse and human VSMCs, we found that TDAG51 is induced in VSMCs by P i and is expressed in the medial layer of calcified human vessels. Furthermore, the transcriptional activity of RUNX2 (Runt-related transcription factor 2), a well-established driver of P i -mediated VC, is reduced in TDAG51 −/− VSMCs. To explain these observations, we identified that TDAG51 −/− VSMCs express reduced levels of the type III sodium-dependent P i transporter, Pit-1, a solute transporter, a solute transporter, a solute transporter responsible for cellular P i uptake. Significantly, in response to hyperphosphatemia induced by vitamin D 3 , medial VC was attenuated in TDAG51 −/− mice.
Our studies highlight TDAG51 as an important mediator of P i -induced VC in VSMCs through the downregulation of Pit-1. As such, TDAG51 may represent a therapeutic target for the prevention of VC and cardiovascular disease in patients with chronic kidney disease.