Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation

Kidney Int. 2014 Aug;86(2):286-93. doi: 10.1038/ki.2013.530. Epub 2014 Jan 15.

Abstract

In chronic kidney disease, vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein, are largely uncarboxylated indicating that functional vitamin K deficiency may contribute to uremic vascular calcification. Since the effects of uremia on the vitamin K cycle are unknown, we investigated the influence of uremia and vitamin K supplementation on the activity of the vitamin K cycle and extraosseous calcification. Uremia was induced in rats by an adenine-supplemented diet and vitamin K1 or K2 was administered over 4 and 7 weeks. After 4 weeks of adenine diet, the activity of the vitamin K cycle enzyme γ-carboxylase but not the activities of DT-diaphorase or vitamin K epoxide reductase were reduced. Serum levels of undercarboxylated matrix Gla protein increased, indicating functional vitamin K deficiency. There was no light microscopy-detectable calcification at this stage but chemically determined aortic and renal calcium content was increased. Vitamin K treatment reduced aortic and renal calcium content after 4 weeks. Seven weeks of uremia induced overt calcification in the aorta, heart, and kidneys; however, addition of vitamin K restored intrarenal γ-carboxylase activity and overstimulated it in the liver along with reducing heart and kidney calcification. Thus, uremic vitamin K deficiency may partially result from a reduction of the γ-carboxylase activity which possibly contributes to calcification. Pharmacological vitamin K supplementation restored the vitamin K cycle and slowed development of soft tissue calcification in experimental uremia.

MeSH terms

  • Animals
  • Aorta / metabolism
  • Calcinosis / etiology
  • Calcinosis / metabolism
  • Calcinosis / prevention & control
  • Calcium-Binding Proteins / blood
  • Carbon-Carbon Ligases / genetics
  • Carbon-Carbon Ligases / metabolism
  • Extracellular Matrix Proteins / blood
  • Kidney / metabolism
  • Liver / metabolism
  • Male
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • Rats
  • Rats, Wistar
  • Uremia / complications
  • Uremia / drug therapy*
  • Uremia / metabolism*
  • Vitamin K / administration & dosage*
  • Vitamin K / metabolism*
  • Vitamin K 1 / metabolism
  • Vitamin K 2 / metabolism
  • Vitamin K Deficiency / blood
  • Vitamin K Deficiency / metabolism

Substances

  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • matrix Gla protein
  • Vitamin K 2
  • Vitamin K
  • Vitamin K 1
  • NAD(P)H Dehydrogenase (Quinone)
  • Carbon-Carbon Ligases
  • glutamyl carboxylase