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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #228060
Title: Inter-relationship of vitamins A, D and K in incidence of renal calcification in A/J mice

Author
item FU, XUEYAN - TUFTS UNIVERSITY
item Wang, Xiang-Dong
item MERNITZ, HEATHER - TUFTS UNIVERSITY
item WALLIN, REIDAR - WAKE FOREST UNIVERSITY
item SHEA, M - TUFTS UNIVERSITY
item Booth, Sarah

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/28/2008
Publication Date: 12/1/2008
Citation: Fu, X., Wang, X., Mernitz, H., Wallin, R., Booth, S.L. 2008. Interrelationship of vitamins A, D and K in incidence of renal calcification in A/J mice. Journal of Nutrition. 138:2337-2341.

Interpretive Summary: In mice, very high doses of the active form of vitamin D [1,25(OH)2D3] causes kidney calcification whereas high doses of an active form of vitamin A (9-cis RA) inhibits the calcification. It is not known if the mechanism underlying this interaction between vitamins A and D also involves vitamin K and the vitamin K-dependent protein, Matrix Gla protein (MGP). We assessed the amount of functional MGP, and vitamin K concentrations [phylloquinone (PK) as well as its conversion product, menaquinone-4 (MK-4)] in kidneys obtained from male mice fed four doses of vitamin D, with and without vitamin A. The vitamin D increased the amount of both functional and nonfunctional MGP. In contrast, vitamin A suppressed the production of nonfunctional MGP and increased the production of the functional MGP. Although all diets contained equal amounts of vitamin K, there was an increase in the conversion of one form of vitamin K (PK) to another (MK-4) in response to vitamin D, whereas the vitamin A reduced total vitamin K concentrations. These data suggest that vitamin A suppressed vitamin D-induced kidney calcification by increasing the functional forms of MGP, with a concomitant decrease in the non-functional forms of MGP. The mechanisms by which vitamins A and D influenced functionality of MGP and vitamin K concentrations warrant further investigation.

Technical Abstract: Matrix gamma-carboxyglutamic acid protein (MGP), a vitamin K-dependent protein, is involved in regulation of tissue calcification. In mice, 9-cis retinoic acid (9-cis RA) mitigates 1alpha, 25 dihydroxyvitamin D3 [1,25(OH)2D3]-induced renal calcification. It is not known if the mechanism(s) underlying this calcification involves vitamin K status and gamma-carboxylation of MGP. We assessed gamma-carboxylation and expression of MGP, and vitamin K concentrations [phylloquinone (PK) as well as its conversion product, menaquinone-4 (MK-4)] in renal and hepatic tissues obtained from A/J male mice fed four doses of 1,25(OH)2D3 (0, 2,5, 5.0 and 10.0 µg/kg diet), with and without 9-cis RA (15 mg/kg diet). The 1,25(OH)2D3 increased renal MGP mRNA and protein levels, and in particular, uncarboxylated MGP (ucMGP, approximately 130-280% increase; cMGP, approximately 40-80% increase]. While 9-cis RA alone had no effect on expression and protein levels of renal MGP, 9-cis RA attenuated the higher levels of ucMGP and MGP mRNA expression induced by 1,25(OH)2D3. Although all diets contained equal amounts of PK, there was a dose-dependent increase in renal and hepatic conversion of PK to MK-4 in response to 1,25(OH)2D3, whereas the 9-cis RA reduced total vitamin K concentrations. These data suggest that 9-cis RA mitigated 1,25(OH)2D3-induced renal calcification by increasing vitamin K-dependent cMGP, with a concomitant decrease in ucMGP. The mechanisms by which 9-cis RA and 1,25(OH)2D3 influenced gamma-carboxylation of MGP and vitamin K concentrations warrant further investigation.