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Calcitriol Accelerates Vascular Calcification Irrespective of Vitamin

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Calcitriol Accelerates Vascular Calcification Irrespective of Vitamin Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/06/14/jpet.117.247270.DC1 1521-0103/366/3/433–445$35.00 https://doi.org/10.1124/jpet.117.247270 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 366:433–445, September 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Calcitriol Accelerates Vascular Calcification Irrespective of Vitamin K Status in a Rat Model of Chronic Kidney Disease with Hyperphosphatemia and Secondary Hyperparathyroidism s Kristin M. McCabe, Jason G. Zelt, Martin Kaufmann, Kimberly Laverty, Emilie Ward, Henry Barron, Glenville Jones, Michael A. Adams, and Rachel M. Holden Departments of Biomedical and Molecular Sciences (K.M.M., J.G.Z., M.K., K.L., E.W., H.B., G.J., M.A.A.) and Medicine (G.J., R.M.H.), Queen’s University, Kingston, Ontario, Canada Received February 6, 2018; accepted May 11, 2018 Downloaded from ABSTRACT Patients with chronic kidney disease (CKD) have a markedly both lower (20 ng/kg) and moderate (80 ng/kg) doses in- increased risk for developing cardiovascular disease. Non- creased the severity of vascular calcification, and contrary to traditional risk factors, such as increased phosphate retention, our hypothesis this was not significantly improved by high increased serum fibroblast growth factor 23 (FGF-23), and defi- dietary vitamin K1. Calcitriol had a dose-dependent effect on: jpet.aspetjournals.org ciencies in vitamins D and K metabolism, likely play key roles in 1) lowering serum parathyroid hormone, 2) increasing serum the development of vascular calcification during CKD progres- calcium, and 3) increasing serum FGF-23. Calcitriol treatment sion. Calcitriol [1,25-(OH)2-D3] is a key transcriptional regulator of significantly increased aortic expression of the calcification matrix Gla protein, a vitamin K–dependent protein that inhibits genes Runx2 and Pit-1. These data also implicate impaired vascular calcification. We hypothesized that calcitriol treatment vitamin D catabolism in CKD, which may contribute to the would inhibit the development of vascular calcification and this development of calcitriol toxicity and increased vascular calci- inhibition would be dependent on vitamin K status in a rat model fication. The present findings demonstrate that in an adenine- of CKD. Rats were treated with dietary adenine (0.25%) to induce induced rat model of CKD calcitriol treatment at doses as low as at ASPET Journals on September 24, 2021 CKD, with either 0, 20, or 80 ng/kg of calcitriol with low or high 20 ng/kg can increase the severity of vascular calcification dietary vitamin K1 (0.2 or 100 mg/kg) for 7 weeks. Calcitriol at regardless of vitamin K status. Introduction et al., 2005; Briet et al., 2006). Fibroblast growth factor 23 (FGF-23) is a hormone that regulates phosphate homeo- Chronic kidney disease (CKD) affects approximately 13% of stasis and is also elevated in the early stages of CKD. Some the Western population (Coresh et al., 2007; Hill et al., 2016). studies also suggest that FGF-23 could be an independent Patients with CKD have a marked increased risk of develop- risk factor for cardiovascular disease and mortality (Gutiérrez ing cardiovascular disease and are more likely to die of et al., 2008; Faul et al., 2011; Isakova et al., 2011). cardiovascular disease before ever requiring renal replace- Vitamin D also plays a key role in calcium/phosphate ment therapy (Andrade and Ignaszewki, 2008). In addition to homeostasis, and it is well-recognized that vitamin D metabo- Framingham risk factors, CKD patients also have many lism becomes impaired with the development of CKD. Circu- nontraditional risk factors including disorders in calcium lating calcitriol [1,25-(OH)2-D3], the active vitamin D hormone, and phosphate metabolism, which lead to the development is derived from 25-OH-D3 via renal CYP27B1 and regulates of vascular calcification (VC). VC occurs when calcium- calcium and phosphate homeostasis in concert with parathy- phosphate crystals deposit within the medial layer of the roid hormone (PTH) and FGF-23 (Fig. 11A) (Crenshaw et al., vasculature leading to an increase in vessel stiffness, a 2011; Quarles, 2012). Many studies support the finding that, decrease in arterial compliance, and an increase in cardio- together, a loss of renal CYP27B1 activity (due to inhibition by vascular and all-cause mortality (London et al., 2003). Multi- FGF-23 and loss of renal mass) (Petkovich and Jones, 2011; ple studies have confirmed associations between the extent of Nigwekar et al., 2012) and a reduction in the levels of 25-OH-D3 VC and mortality in CKD patients (Guérin et al., 2001, 2006, (Nigwekar et al., 2012) lead to severe calcitriol deficiency. In 2008; London et al., 2001, 2003; Safar et al., 2002; Pannier addition, studies support upregulation of CYP24A1, the enzyme responsible for catabolism of 25-OH-D3 and 1,25-(OH)2-D3; The authors acknowledge the financial support provided by the Heart and however, the levels of these metabolites appear to be low, Stroke Foundation of Ontario, the Kidney Foundation of Canada, and the suggesting that vitamin D catabolism is dysregulated in Canadian Institute of Health Research. https://doi.org/10.1124/jpet.117.247270. CKD (Helvig et al., 2010; Jones et al., 2012). To the best of s This article has supplemental material available at jpet.aspetjournals.org. our knowledge, the impact of calcitriol therapy on the ABBREVIATIONS: CKD, chronic kidney disease; FGF-23, fibroblast growth factor 23; MGP, matrix Gla protein; PTH, parathyroid hormone; VC, vascular calcification. 433 434 McCabe et al. upregulation of CYP24A1 and catabolism of vitamin D cycle. The animals used in this experiment were treated in accor- substrates has not been studied in a CKD model. dance with the Canadian Council on Animal Care ethical guidelines There remains considerable debate regarding the safety of of animal care, handling, and termination. vitamin D treatment in this population. A number of clinical Treatment Groups. An animal model of CKD was employed, studies have found that treating patients with vitamin D using dietary adenine as described previously (McCabe et al., 2013; Shobeiri et al., 2013) and a modified version of the adenine model receptor activators, such as calcitriol [1,25-(OH) -D ], ver- 2 3 described by Price et al. (2006). At the start of the experiments, normal sus no treatment provides a survival advantage for early Purina Rat Chow was exchanged with a specially formulated stage CKD and end-stage kidney disease patients (Teng (but nutritionally balanced) diet (Harlan, Teklad, Madison, WI) on et al., 2003, 2005; Melamed et al., 2006; Tentori et al., 2006; which the animals were maintained. The specially formulated diet Levin et al., 2008; Naves-Díaz et al., 2008; Wolf et al., 2008; contained either 0.25% adenine (CKD) or 0% adenine (control) along Nigwekar et al., 2012). However, despite these data, treat- with 1% phosphate, 1% calcium, 0.2 mg/kg vitamin K1 (low vitamin ment of CKD patients with calcitriol is primarily directed K1), 1 IU/g vitamin D, and 6% protein. Male Sprague-Dawley rats at targeting specific PTH levels. This hesitation to treat (beginning at 14 weeks of age) were divided into groups receiving CKD patients with calcitriol may be a consequence of a either 0.25% adenine (CKD) or no adenine (control). Serum number of studies in vitro and in animal models of CKD creatinine levels were measured after 3 weeks and animals were stratified into one of five treatment groups to ensure each group had that suggest calcitriol promotes VC (Inagaki et al., 1995; equivalent kidney dysfunction. For the next 4 weeks, animals were Haffner et al., 2005; Henley et al., 2005; Wu-Wong et al., maintained on their CKD diet with either 0, 20, or 80 ng/kg body Downloaded from 2006b; Terai et al., 2009). However, emerging preclinical weight calcitriol maintained on low vitamin K1, or 20 and 80 ng/kg data suggest that treatment with lower doses of calcitriol can calcitriol with the addition of high dietary vitamin K1, 100 mg/kg inhibit VC (Mathew et al., 2008; Lau et al., 2012). One explana- (Fig. 1, n 5 8/group, N 5 40). An additional group of eight rats was tion is that calcitriol alters vascular susceptibility to calcifi- maintained on a control diet (no adenine). Weights and food intake cation in a dose- and microenvironment-dependent manner, were monitored on a daily basis, and animals were supplemented with where decreases and increases beyond the optimal therapeutic normal chow and/or Nutri-Cal if their weight loss reached 10%. There window promote VC (Razzaque, 2011; Rodriguez et al., 2011). is no vitamin K or calcitriol in Nutri-Cal. The high vitamin K1 dose jpet.aspetjournals.org Calcitriol is a known transcriptional regulator of matrix Gla (100 mg/kg of diet) was selected based on previous work that demonstrated this dose of K1 blunted the development of VC in an protein (MGP) in vascular smooth muscle cells (Farzaneh-Far adenine-induced rat model of CKD (McCabe et al., 2013; Kaesler et al., et al., 2001; Proudfoot and Shanahan, 2006), bone cells (Fraser 2014). The low vitamin K dose (0.2 mg/kg) was chosen to create a mild et al., 1988), and kidney (Fu et al., 2008). MGP is a vitamin deficiency state while maintaining coagulation and was based on K-dependent protein and a potent inhibitor of VC (Luo et al., previous work (Carrié et al., 2004; Booth et al., 2008; McCabe et al., 1997). The g-carboxylation of five Gla domains by the enzyme 2013; Shobeiri et al., 2013). At euthanasia, approximately 6 ml of blood g-glutamyl carboxylase, which requires vitamin K as a cofac- was drawn using a 22 g hypodermic needle inserted into the left at ASPET Journals on September 24, 2021 tor, is critical to the calcium binding function of MGP ventricle of the heart while the animal was under isoflurane-induced (Krueger et al., 2009; Holden et al., 2012).
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