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TDAG51 (T-Cell Death-Associated Gene 51) Is a Key Modulator of Vascular Calcification and Osteogenic Transdifferentiation of Arterial Smooth Muscle Cells.
Platko, Khrystyna; Lebeau, Paul F; Gyulay, Gabriel; Lhoták, Sárka; MacDonald, Melissa E; Pacher, Giusepina; Hyun Byun, Jae; Boivin, Felix J; Igdoura, Suleiman A; Cutz, Jean-Claude; Bridgewater, Darren; Ingram, Alistair J; Krepinsky, Joan C; Austin, Richard C.
Afiliação
  • Platko K; From the Division of Nephrology, Department of Medicine (K.P., P.F.L., G.G., S.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.
  • Lebeau PF; From the Division of Nephrology, Department of Medicine (K.P., P.F.L., G.G., S.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.
  • Gyulay G; From the Division of Nephrology, Department of Medicine (K.P., P.F.L., G.G., S.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.
  • Lhoták S; From the Division of Nephrology, Department of Medicine (K.P., P.F.L., G.G., S.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.
  • MacDonald ME; From the Division of Nephrology, Department of Medicine (K.P., P.F.L., G.G., S.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.
  • Pacher G; From the Division of Nephrology, Department of Medicine (K.P., P.F.L., G.G., S.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.
  • Hyun Byun J; From the Division of Nephrology, Department of Medicine (K.P., P.F.L., G.G., S.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.
  • Boivin FJ; Department of Pathology and Molecular Medicine (F.J.B., S.A.I., D.B.), McMaster University Medical Centre, Hamilton, ON, Canada.
  • Igdoura SA; Department of Pathology and Molecular Medicine (F.J.B., S.A.I., D.B.), McMaster University Medical Centre, Hamilton, ON, Canada.
  • Cutz JC; Department of Biology (S.A.I.), McMaster University Medical Centre, Hamilton, ON, Canada.
  • Bridgewater D; Department of Pathology and Molecular Medicine (J.-C.C.), McMaster University, and The Research Institute of St. Joseph's Hamilton, ON, Canada.
  • Ingram AJ; Department of Pathology and Molecular Medicine (F.J.B., S.A.I., D.B.), McMaster University Medical Centre, Hamilton, ON, Canada.
  • Krepinsky JC; From the Division of Nephrology, Department of Medicine (K.P., P.F.L., G.G., S.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.
  • Austin RC; From the Division of Nephrology, Department of Medicine (K.P., P.F.L., G.G., S.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.
Arterioscler Thromb Vasc Biol ; 40(7): 1664-1679, 2020 07.
Article em En | MEDLINE | ID: mdl-32434409
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Osteogênese / Fatores de Transcrição / Miócitos de Músculo Liso / Transdiferenciação Celular / Calcificação Vascular / Músculo Liso Vascular Limite: Aged / Animals / Female / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Osteogênese / Fatores de Transcrição / Miócitos de Músculo Liso / Transdiferenciação Celular / Calcificação Vascular / Músculo Liso Vascular Limite: Aged / Animals / Female / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article