The Role of Vitamin K in Vascular Calcification in a Rat Model of Chronic Kidney Disease
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Chronic kidney disease (CKD) affects approximately 3 million Canadians and these patients have a markedly increased risk of developing cardiovascular disease. CKD patients have abnormal mineral metabolism and vitamin K status; dysfunctions that can accelerate the rate of vascular calcification. Matrix Gla protein (MGP) is a key tissue based inhibitor of calcification and is dependent on vitamin K for activity. In this thesis, an adenine-induced rat model of CKD was used to characterize quantitatively and temporally the impact of changing vitamin K status on the susceptibility of vessels to calcification. Treatment with the vitamin K antagonist warfarin, at therapeutic levels, significantly increased vessel calcification and the attendant circulatory consequences (higher pulse pressure and pulse wave velocity) whereas treatment with dietary vitamin K attenuated the pathogenesis. Vitamin K (K1) treatment increased the tissue levels of both forms of vitamin K (K1 and MK-4) in all the tissues studied. Vitamin K metabolism was clearly altered by CKD, in that there was a shift to lower K1 and higher MK-4 tissue content, resulting in an increased MK-4:K1 ratio. Although somewhat paradoxical, a decrease in the expression level of the MK-4 synthesizing enzyme UBIAD1 and the vitamin K recycling enzyme VKOR was found. This latter finding suggests that increased MK-4 was not due to an increase in production but rather to a decrease in utilization of MK-4. Patients with CKD are also known to be deficient in calcitriol. In this thesis the impact of two doses of calcitriol (20 ng/kg and 80 ng/kg), in the presence of low or high vitamin K status, on CKD-induced vascular calcification was assessed. Both calcitriol doses increased the severity of calcification regardless of vitamin K status. That is, contrary to the hypothesis, high dietary vitamin K1 was unable to attenuate the pro-calcification stimulus of calcitriol, and furthermore, warfarin treatment did not worsen it. The basis for these unanticipated findings points to the obese phenotype of the animals used potentially masking the potential benefits of calcitriol treatments, although this concept requires further study. Although several unexpected findings occurred, this thesis still fills some key gaps in knowledge pertaining to the role of vitamin K status in the development of vascular calcification during CKD and as a therapeutic intervention.