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Published on: May 31, 2016
TDAG51 (T-Cell Death-Associated Gene 51) Is a Key Modulator of Vascular Calcification and Osteogenic
Khrystyna Platko1, Paul F Lebeau1, Gabriel Gyulay1
1From the Division of Nephrology, Department of Medicine (K.P., P.F.L., G.G., Š.L., M.E.M., G.P., J.H.B., A.J.I., J.C.K., R.C.A.), McMaster University, and The Research Institute of St. Joseph's Hamilton, ON, Canada.
Insights
T-cell death-associated gene 51 (TDAG51) mediates inorganic phosphate-induced vascular calcification in chronic kidney disease by downregulating Pit-1. TDAG51 inhibition may prevent vascular calcification and cardiovascular disease.
Area of Science:
- Nephrology
- Cardiovascular Medicine
- Cell Biology
Background:
- Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD) patients.
- Medial vascular calcification (VC) is a hallmark of advanced CKD, predicting mortality.
- Elevated inorganic phosphate (Pi) drives VSMC-to-osteoblast transition, causing VC in CKD.
Purpose of the Study:
- To investigate the role of T-cell death-associated gene 51 (TDAG51) in medial VC development in CKD.
- To elucidate the molecular mechanisms by which TDAG51 influences Pi-induced VC.
Main Methods:
- Primary mouse and human vascular smooth muscle cells (VSMCs) were used.
- TDAG51 expression and its effect on Pi uptake and RUNX2 activity were analyzed.
- VC was assessed in TDAG51 knockout (TDAG51-/-) mice under hyperphosphatemic conditions.
Main Results:
- TDAG51 is induced by Pi in VSMCs and present in calcified human vessels.
- TDAG51 deficiency reduced Pi-induced RUNX2 activity and Pit-1 transporter expression in VSMCs.
- TDAG51-/- mice exhibited attenuated medial VC during hyperphosphatemia.
Conclusions:
- TDAG51 is a key mediator of Pi-induced VC in VSMCs, acting via Pit-1 downregulation.
- TDAG51 represents a potential therapeutic target for preventing VC and CVD in CKD patients.
Objective:
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 (Pi) 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 Pi 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 Pi-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 Pi transporter, Pit-1, a solute transporter, a solute transporter, a solute transporter responsible for cellular Pi uptake. Significantly, in response to hyperphosphatemia induced by vitamin D3, medial VC was attenuated in TDAG51-/- mice.
Conclusions:
Our studies highlight TDAG51 as an important mediator of Pi-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.
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