Kidney Week

Abstract: SA-OR102

Dietary Magnesium Prevents Vascular Calcification and Bone Mineralization in Klotho Knock-Out Mice

Session Information

• Vascular Calcification, FGF-23, and Phosphate
  October 27, 2018 | Location: 33C, San Diego Convention Center
  Abstract Time: 05:18 PM - 05:30 PM

Category: Bone and Mineral Metabolism

• 401 Bone and Mineral Metabolism: Basic

Authors

• Ter Braake, Anique D., Radboud University Medical Center, Nijmegen, Netherlands

Anique D. Ter Braake, MS



• Alkema, Wynand, Radboud University Medical Center, Nijmegen, Netherlands

Wynand Alkema,

• Hoenderop, Joost, Radboud University Medical Center, Nijmegen, Netherlands

Joost Hoenderop,

• De Baaij, Jeroen H.F., Radboud University Medical Center, Nijmegen, Netherlands

Jeroen H.F. De Baaij,

Background

Klotho is a key modulator of the phosphate (Pi) and calcium (Ca²⁺) balance and is diminished in chronic kidney disease (CKD). Klotho knock-out (^-/-) mice are therefore an important model for CKD, mimicking all essential features including hyperphosphatemia and development of calcification. In CKD, serum magnesium (Mg²⁺) inversely correlates with incidence and severity of vascular calcification. The mechanisms by which Mg²⁺prevents vascular calcification are poorly understood. Therefore, this study aims to determine the effects of Mg²⁺on development of aortic calcification using Klotho^-/-mice.

Methods

Klotho^-/-and Klotho^+/+mice were fed a normal (0.05% w/w) or high (0.48% w/w) Mg²⁺diet from birth. Aortic calcification was detected by Von Kossa staining and RNA-sequencing was performed. Serum electrolyte and hormone concentrations were determined. MicroCT was used to study bone integrity.

Results

Von Kossa staining revealed that aortic calcification developed extensively in Klotho^-/-mice on a normal Mg²⁺diet and was absent in Klotho^+/+mice. Strikingly, high Mg²⁺diet prevented calcification in Klotho^-/-mice. Moreover, Mg²⁺rescued increased expression of RUNX2 and osteopontin as well as upregulation of matrix gla protein, demonstrating the preventive effect of Mg²⁺on pro-osteogenic signaling. Potential novel mechanisms by which Mg²⁺prevented calcification were studied by RNA sequencing, revealing that pathways mediating inflammation and extracellular matrix remodeling enriched in Klotho^-/-mice were reversed by Mg²⁺. Though Mg²⁺prevented calcification, klotho^-/-mice on high Mg²⁺diet had reduced weight and smaller stature. Interestingly, high Mg²⁺impaired bone formation in Klotho^-/-mice as femoral mineral-bone density decreased by 20% compared to mice on normal Mg²⁺ diet. High Mg²⁺did not change known mineralization modulators parathyroid hormone, 1.25-dihydroxyvitamin D and Ca²⁺in serum. Interestingly, Mg²⁺prevented calcification despite increasing fibroblast growth factor-23 and Pi concentration in Klotho^-/-mice.

Conclusion

This study shows that Mg²⁺prevented vascular calcification in Klotho^-/-mice. Importantly, Mg²⁺prevented mineralization in the aortic media as well as bone, potentially involving anti-inflammatory signaling and disruption of extracellular matrix remodeling.

Funding

• Government Support - Non-U.S.