TDAG51 (T-Cell Death-Associated Gene 51) Is a Key Modulator of Vascular Calcification and Osteogenic Transdifferentiation of Arterial Smooth Muscle Cells

Arterioscler Thromb Vasc Biol. 2020 Jul;40(7):1664-1679. doi: 10.1161/ATVBAHA.119.313779. Epub 2020 May 21.

Abstract

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.

Keywords: hyperphosphatemia; inorganic phosphate transporter; osteoblasts; risk factor; vascular calcification; vascular smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cell Transdifferentiation*
  • Cells, Cultured
  • Cholecalciferol
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Humans
  • Hyperphosphatemia / chemically induced
  • Hyperphosphatemia / metabolism
  • Hyperphosphatemia / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • Osteogenesis*
  • Phosphates / metabolism
  • Signal Transduction
  • Sodium-Phosphate Cotransporter Proteins, Type III / genetics
  • Sodium-Phosphate Cotransporter Proteins, Type III / metabolism
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Vascular Calcification / genetics
  • Vascular Calcification / metabolism*
  • Vascular Calcification / pathology
  • Vascular Calcification / prevention & control

Substances

  • Core Binding Factor Alpha 1 Subunit
  • PHLDA1 protein, human
  • Phlda1 protein, mouse
  • Phosphates
  • RUNX2 protein, human
  • Runx2 protein, mouse
  • SLC20A1 protein, human
  • Slc20a1 protein, mouse
  • Sodium-Phosphate Cotransporter Proteins, Type III
  • Transcription Factors
  • Cholecalciferol

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