9-Cis retinoic acid reduces 1alpha,25-dihydroxycholecalciferol-induced renal calcification by altering vitamin K-dependent gamma-carboxylation of matrix gamma-carboxyglutamic acid protein in A/J male mice.
Matrix gamma-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 1alpha,25-dihydroxycholecalciferol [1,25(OH)(2)D3]-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 gamma-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)(2)D3 (2.5 microg/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, gamma-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)(2)D3-induced renal calcification by modifying the 1,25(OH)(2)D3-induced increase in ucMGP. The mechanisms by which 9-cis RA and 1,25(OH)(2)D3 alter vitamin K concentrations warrant further investigation.
Fu
Xueyan
X
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
Wang
Xiang-Dong
XD
Mernitz
Heather
H
Wallin
Reidar
R
Shea
M Kyla
MK
Booth
Sarah L
SL
D000077556:Alitretinoin; D000818:Animals; D001483:Base Sequence; D002114:Calcinosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002117:Calcitriol / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019735:Carbon-Carbon Ligases / Q000378:metabolism*; D002273:Carcinogens / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity; D017931:DNA Primers / Q000235:genetics; D019587:Dietary Supplements; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D009602:Nitrosamines / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology*; D014812:Vitamin K / Q000378:metabolism; D000097568:Matrix Gla Protein
D000077556:Alitretinoin; D002117:Calcitriol; D002135:Calcium-Binding Proteins; D019735:Carbon-Carbon Ligases; D002273:Carcinogens; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D009602:Nitrosamines; D012333:RNA, Messenger; D014212:Tretinoin; D014812:Vitamin K; D000097568:Matrix Gla Protein; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C020660:glutamyl carboxylase