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.
Abstract

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