@article {McCabejpet.117.247270, author = {Kristin M McCabe and Jason G Zelt and Martin Kaufmann and Kimberly Laverty and Emilie Ward and Henry Barron and Glenville Jones and Michael A Adams and Rachel M Holden}, title = {Calcitriol accelerates vascular calcification irrespective of vitamin K status in a rat model of CKD with hyperphosphatemia and secondary hyperparathyroidism}, elocation-id = {jpet.117.247270}, year = {2018}, doi = {10.1124/jpet.117.247270}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Patients with chronic kidney disease have a markedly increased risk for developing cardiovascular disease. Non-traditional risk factors, such as increased phosphate retention, and deficiencies in vitamins D and K metabolism, likely play key roles in the development of vascular calcification during CKD progression. Calcitriol (1,25-(OH)2-D3) is a key transcriptional regulator of Matrix Gla protein (MGP), a vitamin K dependent protein that inhibits vascular calcification. The objective of this study was to determine if calcitriol treatment could inhibit the development of vascular calcification and if this inhibition was dependent on vitamin K status in a rat model of CKD. Rats were treated with dietary adenine (0.25\%) to induce CKD, with either 0, 20 or 80 ng/kg of calcitriol with low or high dietary vitamin K1 (0.2 or 100 mg/kg) for 7 weeks. Calcitriol at both low (20 ng/kg) and moderate (80 ng/kg) doses increased the severity of vascular calcification and, contrary to our hypothesis, this was unaffected by high dietary vitamin K1. Calcitriol had a dose-dependent effect on: (i) lowering serum PTH, (ii) increasing serum calcium and (iii) increasing serum FGF-23. Calcitriol treatment significantly increased aortic expression of the calcification genes Runx2 and Pit-1. This data also implicates impaired vitamin D catabolism in CKD, which may contribute to the development of calcitriol toxicity and increased vascular calcification. The present findings demonstrate that in an adenine-induced rat model of CKD, calcitriol treatment at doses as low as 20 ng/kg can increase the severity of vascular calcification regardless of vitamin K status.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2018/06/14/jpet.117.247270}, eprint = {https://jpet.aspetjournals.org/content/early/2018/06/14/jpet.117.247270.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }