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Wu-Wong J.R.,University of Illinois at Chicago | Nakane M.,VidaGene | Gagne G.D.,Abbott Laboratories | Brooks K.A.,Abbott Laboratories | Noonan W.T.,Abbott Laboratories
International Journal of Endocrinology | Year: 2010

Vitamin D receptor agonists (VDRAs) directly suppress parathyroid hormone (PTH) mRNA expression. Different VDRAs are known to have differential effects on serum calcium (Ca), which may also affect serum PTH levels since serum Ca regulates PTH secretion mediated by the Ca-sensing receptor (CaSR). In this study, we compared the effects of paricalcitol and doxercalciferol on regulating serum Ca and PTH, and also the expression of PTH, VDR, and CaSR mRNA. The 5/6 nephrectomized (NX) Sprague-Dawley rats on a normal or hyperphosphatemia- inducing diet were treated with vehicle, paricalcitol, or doxercalciferol for two weeks. Both drugs at the tested doses (0.042-0.33 μg/kg) suppressed PTH mRNA expression and serum PTH effectively in the 5/6 NX rats, but paricalcitol was less potent in raising serum Ca than doxercalciferol. In pig parathyroid cells, paricalcitol and the active form of doxercalciferol induced VDR translocation from the cytoplasm into the nucleus, suppressed PTH mRNA expression and inhibited cell proliferation in a similar manner, although paricalcitol induced the expression of CaSR mRNA more effectively. The multiple effects of VDRAs on modulating serum Ca, parathyroid cell proliferation, and the expression of CaSR and PTH mRNA reflect the complex involvement of the vitamin D axis in regulating the mineral homeostasis system. © 2010 J. RuthWu-Wong et al.

Wu-Wong J.R.,University of Illinois at Chicago | Nakane M.,VidaGene | Chen Y.-W.,VidaGene
Life Sciences | Year: 2013

Aims To investigate whether the frequency of monitoring paricalcitol's impact on serum calcium (Ca), phosphorus and PTH in current clinical practice is sufficient by mapping the time-dependent effects of paricalcitol on these parameters. Main methods The 5/6 nephrectomized (NX) male, Sprague-Dawley rats with established uremia were treated with vehicle or paricalcitol (0.16 μg/kg, i.p., 3 ×/week). On Day 0 (before treatment), Days 12 and 13 after treatment, and also at 0, 1, 4, 8, 16, 24 h after the last dosing, blood and small intestine samples were collected. Key findings Serum creatinine and blood urea nitrogen levels were significantly elevated in 5/6 NX rats. Significant increases were observed in serum Ca while PTH decreased by > 90% when the parameters were determined at 12 or 13 days after paricalcitol dosing. Paricalcitol caused a step-wise increase in serum Ca levels at 1-24 h following dosing, reduced serum PTH levels with PTH values ranging from 1.06 ± 0.06 to 26.7 ± 25.7 pg/ml (vs. 152 ± 15 pg/ml in Sham rats), but did not affect serum phosphorus in a time-dependent manner. Consistent with the serum Ca data, paricalcitol significantly induced the intestinal expression of Calb3 and TRPV6, genes involved in intestinal Ca transport, and also significantly induced the intestinal calcium absorption. Significance Our results suggest that the frequency of monitoring paricalcitol's effect on serum Ca, phosphorus and PTH in current clinical practice seems adequate. Additional clinical trials may be needed to resolve the inconsistent clinical observations about the impact of paricalcitol on serum Ca. © 2012 Elsevier Inc.

Wu-Wong J.R.,University of Illinois at Chicago | Noonan W.,Abbott Laboratories | Nakane M.,VidaGene | Brooks K.A.,Abbott Laboratories | And 3 more authors.
International Journal of Endocrinology | Year: 2010

Endothelial dysfunction increases cardiovascular disease risk in chronic kidney disease (CKD). This study investigates whether VDR activation affects endothelial function in CKD. The 5/6 nephrectomized (NX) rats with experimental chronic renal insufficiency were treated with or without paricalcitol, a VDR activator. Thoracic aortic rings were precontracted with phenylephrine and then treated with acetylcholine or sodium nitroprusside. Uremia significantly affected aortic relaxation (-50.0±7.4% in NX rats versus -96.2±5.3% in SHAM at 30 μM acetylcholine). The endothelial-dependent relaxation was improved to -58.2±6.0% , -77.5±7.3% , and -90.5±4.0% in NX rats treated with paricalcitol at 0.021, 0.042, and 0.083 μg/kg for two weeks, respectively, while paricalcitol at 0.042 μg/kg did not affect blood pressure and heart rate. Parathyroid hormone (PTH) suppression alone did not improve endothelial function since cinacalcet suppressed PTH without affecting endothelial-dependent vasorelaxation. N-omega-nitro-L-arginine methyl ester completely abolished the effect of paricalcitol on improving endothelial function. These results demonstrate that VDR activation improves endothelial function in CKD. © 2010 J. RuthWu-Wong et al.

Wu-Wong J.R.,University of Illinois at Chicago | Chen Y.-W.,VidaGene | Nakane M.,VidaGene | Wolf M.,University of Miami
Cardiovascular Drugs and Therapy | Year: 2011

Purpose: Vitamin D receptor (VDR) activation is associated with cardiovascular benefits in chronic kidney disease patients, but whether VDR's hormone and prehormone exhibit similar effects requires more studies. Methods: Neonatal rat cardiomyocytes were treated with VDR agonists (calcitriol and/or paricalcitol) and the prehormone calcidiol in the presence of aldo (1 μM). The expression of VDR target genes were determined by real-time PCR and Western blotting. The expression and activity of CYP27B1 (the enzyme responsible for converting calcidiol to calcitriol) was measured. Results: Treating cells with aldo (1 μM) for 24 h significantly reduced the VDR mRNA (29%) and protein levels (>90%). Calcitriol and calcidiol induced VDR expression in the presence of aldo with EC50 at 0.3 and 7,952 nM, respectively. Calcitriol, paricalcitol and calcidiol stimulated CYP24A1 (EC50 at 6.4, 4.5 and 992 nM, respectively) and suppressed NPPB expression (IC 50 at 1.9, 0.1 and 210 nM, respectively) in the presence of 1 μM aldo. Neonatal rat cardiomyocytes expressed CYP27B1 and converted calcidiol to calcitriol at a low rate (∼10% in 24 h). Conclusions: VDR hormone calcitriol and its analog paricalcitol exhibit more potent effects than the prehormone calcidiol in cardiomyocytes. © 2011 Springer Science+Business Media, LLC.

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