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Utilice este identificador para citar o enlazar este documento: https://ria.asturias.es/RIA/handle/123456789/13788


Título: The receptor activator of nuclear factor jB ligand receptor leucine-rich repeat-containing G-protein-coupled receptor 4 contributes to parathyroid hormone-induced vascular calcification
Autores: Carrillo‑López, Natalia
Martínez‑Arias, Laura
Alonso-Montes, Cristina
Martín-Carro, Beatriz
Martín-Vírgala, Julia
Ruiz-Ortega, Marta
Fernández-Martín, Jose Luis
Dusso, Adriana
Rodríguez-García, Minerva
Naves-Díaz, Manuel
Cannata-Andía, Jorge B.
Panizo, Sara
Palabras Claves: high phosphorus
leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4)
PTH and vascular calcification
receptor activator of NFjB (RANK)/RANK ligand (RANKL/OPG) system
Fecha Edición: Dic-2020
Editor: Nephrol Dial Transplant
Cita Bibliográfica: doi: 10.1093/ndt/gfaa290
Resumen: Background. In chronic kidney disease, serum phosphorus (P) elevations stimulate parathyroid hormone (PTH) production, causing severe alterations in the bone–vasculature axis. PTH is the main regulator of the receptor activator of nuclear factor jB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, which is essential for bone maintenance and also plays an important role in vascular smooth muscle cell (VSMC) calcification. The discovery of a new RANKL receptor, leucine-rich repeat-containing G-proteincoupled receptor 4 (LGR4), which is important for osteoblast differentiation but with an unknown role in vascular calcification (VC), led us to examine the contribution of LGR4 in high P/high PTH–driven VC. Methods. In vivo studies were conducted in subtotally nephrectomized rats fed a normal or high P diet, with and without parathyroidectomy (PTX). PTX rats were supplemented with PTH(1–34) to achieve physiological serum PTH levels. In vitro studies were performed in rat aortic VSMCs cultured in control medium, calcifying medium (CM) or CM plus 10_7 versus 10_9MPTH. Results. Rats fed a high P diet had a significantly increased aortic calcium (Ca) content. Similarly, Ca deposition was higher in VSMCs exposed to CM. Both conditions were associated with increased RANKL and LGR4 and decreased OPG aorta expression and were exacerbated by high PTH. Silencing of LGR4 or parathyroid hormone receptor 1 (PTH1R) attenuated the high PTH–driven increases in Ca deposition. Furthermore, PTH1R silencing and pharmacological inhibition of protein kinase A (PKA), but not protein kinase C, prevented the increases in RANKL and LGR4 and decreased OPG. Treatment with PKA agonist corroborated that LGR4 regulation is a PTH/PKA-driven process. Conclusions. High PTH increases LGR4 and RANKL and decreases OPG expression in the aorta, thereby favouring VC. The hormone’s direct pro-calcifying actions involve PTH1R binding and PKA activation.
URI: https://ria.asturias.es/RIA/handle/123456789/13788
Aparece en las Colecciones:Sanidad

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