1 2014 Vol: 86(2):286-293. DOI: 10.1038/ki.2013.530

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

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.Keywords: gamma-carboxylase; nephropathy; vascular calcification; vitamin K

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Figures
Figure 1: Overview of the different treatment groups. Seven weeks of treatment contained a 2-week interphase without adenine supplementation. *Protein content was lowered to 2.5% in the 7-week groups (see Supplemetary Table S2 online). All diets contained 5 mg/kg vitamin (Vit) K1 (except diet in group i). Figure 2: Undercarboxylated matrix Gla protein (ucMGP) measured in serum after 4 weeks of treatment. *P<0.05. Figure 3: Hepatic vitamin K content. (a) Vitamin K1 measured in liver tissue after 7 weeks of diet; (b) MK4 measured in liver tissue after 7 weeks of diet. **P<0.01. Figure 4: Quantification of undercarboxylated matrix Gla protein (ucMGP) staining in aortas after 7 weeks of treatment. *P<0.05. Figure 5: The γ-glutamyl carboxylase (GGCX) activity. In kidneys after 4 (a) and 7 (b) weeks and in liver after 4 (c) and 7 (d) weeks (mean±s.d.). *P<0.05 and **P<0.01. Figure 6: The γ-glutamyl carboxylase (GGCX) activity in aortas after 7 weeks (mean±s.d.) of treatment. *P<0.05. Figure 7: The DT-diaphorase activity. In kidneys after 4 (a) and 7 (b) weeks and in liver after 4 (c) and 7 (d) weeks (mean±s.d.). *P<0.05.
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References
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