Kidney Week

Abstract: SA-PO253

Magnesium Supplementation Reduces Vascular Calcification by Activating Calcium-Sensing Receptor (CaSR) in Vascular Smooth Muscle Cells

Session Information

• CKD-MBD: Basic and Translational
  October 26, 2024 | 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

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

Qi Gao, MD, PhD

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

Onur Cil, MD, PhD

Background

Pathological deposition of calcium-phosphate in the arterial wall leads to vascular calcification, which is an important risk factor for cardiovascular mortality in CKD patients. Higher dietary Mg²⁺ intake was shown to reduce vascular calcification and cardiovascular mortality in clinical studies, however the mechanisms of Mg²⁺ effect remain unclear. Extracellular Ca²⁺-sensing receptor (CaSR) is a protein expressed in many tissues including vascular smooth muscle cells (VSMC). Although Ca²⁺ is considered as its main physiological agonist, we recently showed that Mg²⁺ (an often neglected CaSR agonist) is a more potent CaSR activator in certain tissues such as gut and lung.

Methods

We studied the roles of CaSR in therapeutic effects of Mg²⁺ in cell and mouse models of vascular calcification.

Results

In both mouse and human primary aortic smooth muscle cells, calcium-phosphate treatment (3 mM Ca²⁺, 2.5 mM PO₄^3- for 7 days) resulted in marked calcification. Increasing Mg²⁺ in culture media concentration-dependently reduced calcification by up to 90% at 1 mM. The protective effects of Mg²⁺ were essentially abolished by CaSR inhibitor NPS-2143. Mg²⁺ concentration had minimal effects on calcification in primary cells derived from VSMC-specific CaSR knockout mice (SM22-Cre; Casr-flox), confirming key roles of CaSR in its efficacy. CaSR activation assays showed that Mg²⁺ is 2-5 fold more potent CaSR agonist than Ca²⁺ in human and mouse primary VSMC. In high dose vitamin D-induced vascular calcification model, mice fed with low (0.02%) Mg²⁺ diet had severe aortic calcification which was reduced by 32% and 66% in mice fed with normal (0.2%) and high (0.5%) Mg²⁺ diets, respectively. Aortic CaSR protein expression was found to be reduced by 85% and 60% in mice fed with low and normal Mg²⁺ diets, respectively, compared to controls. Co-staining showed that CaSR expression was primarily reduced in calcified areas. High Mg²⁺ diet resulted in largely preserved aortic CaSR expression in mice.

Conclusion

These results collectively suggest that Mg²⁺ is the key CaSR agonist in VSMC for prevention of vascular calcification. Mg²⁺ deficiency results in reduced CaSR activity and expression, which can be restored by its supplementation. Mg²⁺ supplementation can potentially be used as a simple, safe and effective treatment for preventing vascular calcification in CKD.

Funding

• NIDDK Support