Kidney Week

Abstract: SA-PO0286

Magnesium Activates Calcium-Sensing Receptor (CaSR) to Reduce Osteoblastic Differentiation and Calcification in CKD Vasculature

Session Information

• Bone and Mineral Metabolism: Basic Research
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Cil, Onur, University of California San Francisco, San Francisco, California, United States

Onur Cil, MD, PhD

• Gao, Qi, University of California San Francisco, San Francisco, California, United States

Qi Gao, MD, PhD

• Tas, Sadik Taskin, University of California San Francisco, San Francisco, California, United States

Sadik Taskin Tas, MD, PhD

Background

Vascular calcification is an important risk factor for cardiovascular mortality in CKD. Higher dietary magnesium (Mg²⁺) intake was shown to reduce vascular calcification; however, the mechanisms of Mg²⁺ effect remain largely unknown. cAMP is a major driver for osteoblastic differentiation and calcification of vascular smooth muscle cells (VSMC). Extracellular calcium-sensing receptor (CaSR) is a regulator of cAMP pathway and Mg²⁺ is a CaSR agonist. We hypothesized that CaSR activation is a major mechanism for the protective effects of Mg²⁺ in vascular calcification.

Methods

The effects of Mg²⁺ and roles of CaSR were studied in cell and animal models of vascular calcification including a CKD model.

Results

In a primary mouse aortic VSMC calcification model induced by high Ca²⁺ and PO4^2-, increasing Mg²⁺ concentration to physiological levels (0.1 to 1 mM) reduced severity of calcification by up to 90%. Mg²⁺ effect was abolished with CaSR inhibitor NPS-2143 treatment. In primary VSMC from VSMC-specific CaSR knockout mice (SM22-Cre; Casr-flox), Mg²⁺ concentration and CaSR inhibition had minimal effects on calcification. CaSR activation assays showed that Mg²⁺ is a more potent CaSR agonist than Ca²⁺ in VSMC at physiological concentrations seen in plasma. 1 mM Mg²⁺ reduced cAMP levels, CREB phosphorylation and RUNX2 (osteoblastic differentiation marker) expression in VSMC. In adenine-induced CKD model, increasing dietary Mg²⁺ reduced vascular calcification severity by >90 % in wild-type mice with minimal effect in VSMC-specific CaSR knockouts. Higher Mg²⁺ intake in CKD model increased serum Mg²⁺ levels without any changes in serum Ca²⁺, Pi or BUN. In mouse aorta, vascular calcification reduced CaSR expression by 60%, and high Mg²⁺ diet administration resulted in preserved CaSR expression. Lastly, physiological Mg²⁺ concentrations reduced calcification severity by >70% in a primary human aortic VSMC model and Mg²⁺ effect was abolished with CaSR inhibition.

Conclusion

Our results suggest that Mg²⁺ reduces vascular calcification by activating CaSR and preventing osteoblastic differentiation in VSMC. Mg²⁺ supplementation can be a simple and safe treatment for preventing vascular calcification in CKD.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025491pxgat