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Shh-Gli2-Runx2 inhibits vascular calcification.
- Source :
-
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association [Nephrol Dial Transplant] 2024 Jan 31; Vol. 39 (2), pp. 305-316. - Publication Year :
- 2024
-
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.<br />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.<br />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.<br />Conclusions: Our study provided deeper insight to the pathogenesis of VC, and Shh might be a novel potential target for VC treatment.<br /> (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)
- Subjects :
- Humans
Mice
Animals
Hedgehog Proteins genetics
Hedgehog Proteins metabolism
Hedgehog Proteins pharmacology
Phosphorus metabolism
Adenine
Myocytes, Smooth Muscle metabolism
Core Binding Factor Alpha 1 Subunit genetics
Core Binding Factor Alpha 1 Subunit metabolism
Vascular Calcification etiology
Vascular Calcification prevention & control
Vascular Calcification metabolism
Renal Insufficiency, Chronic pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2385
- Volume :
- 39
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
- Publication Type :
- Academic Journal
- Accession number :
- 37451818
- Full Text :
- https://doi.org/10.1093/ndt/gfad165