Shh-Gli2-Runx2 inhibits vascular calcification.
Nephrol Dial Transplant
; 39(2): 305-316, 2024 Jan 31.
Article
en En
| MEDLINE
| ID: mdl-37451818
ABSTRACT
BACKGROUND:
In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and is associated with a higher risk of all-cause mortality. Shh, one ligand for Hedgehog (Hh) signaling, participates in osteogenesis and several cardiovascular diseases. However, it remains unclear whether Shh is implicated in the development of VC.METHODS:
Inorganic phosphorus 2.6 mM was used to induce vascular smooth muscle cells (VSMCs) calcification. Mice were fed with adenine diet supplement with 1.2% phosphorus to induce VC.RESULTS:
Shh was decreased in VSMCs exposed to inorganic phosphorus, calcified arteries in mice fed with an adenine diet, as well as radial arteries from patients with CKD presenting VC. Overexpression of Shh inhibited VSMCs ostosteoblastic differentiation and calcification, whereas its silencing accelerated these processes. Likewise, mice treated with smoothened agonist (SAG; Hh signaling agonist) showed alleviated VC, and mice treated with cyclopamine (CPN; Hh signaling antagonist) exhibited severe VC. Additionally, overexpression of Gli2 significantly reversed the pro-calcification effect of Shh silencing on VSMCs, suggesting that Shh inhibited VC via Gli2. Mechanistically, Gli2 interacted with Runx2 and promoted its ubiquitin proteasomal degradation, therefore protecting against VC. Of interest, the pro-degradation effect of Gli2 on Runx2 was independent of Smurf1 and Cullin4B.CONCLUSIONS:
Our study provided deeper insight to the pathogenesis of VC, and Shh might be a novel potential target for VC treatment.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Insuficiencia Renal Crónica
/
Calcificación Vascular
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nephrol Dial Transplant
Asunto de la revista:
NEFROLOGIA
/
TRANSPLANTE
Año:
2024
Tipo del documento:
Article
País de afiliación:
China