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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

9-Cis Retinoic Acid Reduces 1,25-Dihydroxycholecalciferol-Induced Renal Calcification by Altering Vitamin K-Dependent -Carboxylation of Matrix -Carboxyglutamic Acid Protein in A/J Male Mice^1,2

³ Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111 and ⁴ Internal Medicine, Wake Forest University, Winston-Salem, NC 27157

Matrix -carboxyglutamic acid protein (MGP), a vitamin K-dependent protein, is involved in regulation of tissue calcification. We previously reported that 9-cis retinoic acid (RA) mitigates 1,25-dihydroxycholecalciferol [1,25(OH)₂D3]-induced renal calcification in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer A/J male mouse model. This raised the question if the mechanism(s) underlying this calcification involves vitamin K. We assessed expression and vitamin K dependent -carboxylation of MGP and vitamin K concentrations [phylloquinone (PK), as well as its conversion product, menaquinone-4 (MK-4)] in tissues obtained from NNK-injected A/J male mice fed 1,25(OH)₂D3 (2.5 µg/kg diet; D group) ± RA (15 mg/kg diet) for 20 wk. Renal calcification was only observed in the D group (2/10; 20% of the group). Renal MGP mRNA and uncarboxylated MGP (ucMGP) increased in response to D (P < 0.05) but not in response to RA or RA + D. In contrast, -carboxylated MGP increased to 2.2-fold of the control in response to D+RA (P < 0.05) but not in response to RA or D alone. Although all diets contained equal amounts of PK, the kidney MK-4 concentration was higher in the D group (P < 0.05) and lower in the RA group (P < 0.05) compared with the RA+D or control groups. Renal PK concentrations were lower in the RA and RA+D groups than in the control and D groups (P < 0.05). These data suggest that 9-cis RA mitigated 1,25(OH)₂D3-induced renal calcification by modifying the 1,25(OH)₂D3-induced increase in ucMGP. The mechanisms by which 9-cis RA and 1,25(OH)₂D3 alter vitamin K concentrations warrant further investigation.

^* To whom correspondence should be addressed. E-mail: sarah.booth{at}tufts.edu.

Manuscript received 30 May 2008. Initial review completed 25 June 2008. Revision accepted 28 August 2008.