Tải bản đầy đủ - 0 (trang)
8 Therapeutic Implications: Selective Vitamin D Receptor Activators in CKD

8 Therapeutic Implications: Selective Vitamin D Receptor Activators in CKD

Tải bản đầy đủ - 0trang


J. Bover et al.

[194, 195], – raising the possibility that their actions could be VDR independent -,

it has also been recently shown in a novel organ culture model that direct suppression of PTH gene expression by doxercalciferol (a selective VDR activator) and

25(OH)D requires the VDR [196].

Since an excessive Ca and P loading is the most undesirable untoward effect of

1,25(OH)2D3, especially in patients with CKD, VDR activators have been developed to reduce the capacity to induce in-vivo hypercalcemia, hyperphosphatemia

and hypercalciuria, and thus the concept of selective VDR activators has evolved

[197]. For instance, paricalcitol and maxacalcitol are considered selective VDR

activators because they seem to preferentially effect parathyroid glands by retaining

the action on PTH suppression while having less effect on Ca and P intestinal

absorption or bone resorption [34, 198–200]. Consequently, these selective VDR

activators could possibly avoid deleterious effects derived from serum high levels of

Ca and P, including possible passive extraskeletal calcification in vessels or heart

valves. Potentially, these differential effects could also have an impact on survival.

Experimental studies have shown distinct actions of calcitriol or other VDR activators on extraosseous calcification, the former being a classic dose-dependent inductor of experimental vascular calcification especially in the presence of a high P

exposure, or as a result of vitamin-D-induced systemic accumulation of Ca and P

rather than a local effect on the arterial wall [162, 201–203]. On the other hand,

lower doses of both calcitriol and paricalcitol seemed to be protective probably

through restoration of klotho and osteopontin expression [19, 136, 204]. Thus, a

bimodal effect of VDR activators has been described with regard to regulation of

vascular calcification. This issue is further complicated by the differential expression and regulation of klotho in experimental uremia, and the tissue-dependent

effect of a VDR activator such as paricalcitol, recently described [205]. In this study,

paricalcitol prevented the decrease of klotho in the kidney, increased expression in

the parathyroid, had no effect in the aortic media, but blunted the increase of klotho

in the aortic adventitia –probably expressed by fibroblasts [205].

In general, the experimental data supporting less toxicity of some VDR activators compared with calcitriol are not consistent across studies, but they seem to

support the claim that there is reduced induction of vascular calcification with different VDR activators, favoring paricalcitol [162, 199, 201, 206, 207]. However,

there are no prospective randomized clinical trials that have evaluated the impact of

native vitamin D or VDR activators on human vascular calcification. Finally, a

robust and consistent survival benefit of VDR activators in hemodialysis patients

has been described in several retrospective studies [208, 209], and although it has

been questioned [210], the benefit seemed to be more pronounced in the low-dose

range and among patients who received selective VDR activators [208]. Finally, a

recent meta-analysis including 14 observational studies (194,932 patients) has

shown that therapies with VDR activators are associated with reduced mortality in

CKD patients [211], although another recent meta-analysis and a smaller study in

peritoneal dialysis patients do not confirm these previous results [212, 213]. Again,

no randomized clinical trial has been performed to prove or rule out this survival

hypothesis. Consequently, it is not the time to say that interventions based on


Vitamin D Receptor and Interaction with DNA


vitamin D definitely reduce mortality in patients with CKD, but the opposite cannot

be said yet beyond all reasonable doubt [214]. In fact, given the paucity of good

quality data, the reliability of the pooled results is still uncertain [214], warranting

the need of larger trials on clinically significant hard-outcomes.

The alleged difference among analogs and their effects on different target organs

may be related, among other factors, to different pharmacokinetic/pharmacodynamic properties by distinctly interacting with serum-binding proteins (e.g. affinity

to circulating DBP) or differential metabolism in a tissue-selective manner. For

instance, it has been shown that maxacalcitol has about 400–500 times less binding

affinity to DBP than 1,25(OH)2D3 [215], and thus has a shorter half-life and is

cleared more rapidly from the circulation. It has also been shown that VDR analogs

have a lower affinity for VDR than 1,25(OH)2D3 [216, 217] and differential regulation of 24-hydroxylase in target tissues may also determine the half-life of

1,25(OH)2D3 and analogs [217]. Interestingly, selective VDR activators seem to

interact differentially with VDR coregulators and, based on conformational differences induced by these molecules, gene expression may be modified when the VDR/

RXR complex binds to the VDRE, causing selectively distinct effects on DNA transcription in different cells and tissues [101, 218, 219]. Thus, the diversity of coregulators and multiple multicomponent complexes help explain receptor, target gene

and cell-selective responses to different ligands at the same VDR [73]. As an example, calcitriol has ten times more affinity for binding to the VDR than the selective

VDR activator paricalcitol [199, 216]; nevertheless, this difference in binding affinity is not the same for all body tissues, as the affinity of paricalcitol for the VDR in

the parathyroid glands is three to four times lower than that of 1,25(OH)2D3.

Paricalcitol is less active than 1,25(OH)2D3 in inducing homodimerization (VDR:VD)

and heterodimerization of VDR: receptor-associated coactivator 3 (RAC3), and

more active than calcitriol in inducing heterodimerization of VDR/RXR and VDRglucocorticoid receptor interacting protein 1 (DRIP1) [120]. Clinically, it has been

shown that selective VDR activators allow synthesis and secretion of PTH to be

inhibited more efficiently and with a lower impact on intestinal absorption of Ca and

P [199, 220]. Therefore, they are attributed a lower risk of hypercalcemia, hyperphosphatemia, and elevated Ca x P levels. In a five sixths nephrectomized rat model,

when paricalcitol is compared with calcitriol, its impact at the same doses is three to

four times less than calcitriol on PTH levels and ten times less on Ca and P levels

meaning that paricalcitol can act with a larger therapeutic margin for the prevention

and treatment of secondary hyperparathyroidism in early stages of CKD, as well as

in patients on hemodialysis, and with a lower potential impact on vascular calcification [221, 222]. It has been also shown that switching 1,25(OH)2D3 to selective vitamin D receptor activators such as paricalcitol can help controlling previously

uncontrolled secondary hyperparathyroidism [223]. On the other hand, although

there are no data on this action in humans, Malluche et al. [200] state, based on

experimental data, that the vitamin D analogs paricalcitol and maxacalcitol could

control PTH levels with a lower suppression of bone remodeling.

The differential effects of selective VDR activators have also been seen on gene

expression in various types of cells and tissues, including the expression of


J. Bover et al.

molecules involved in the process of vascular calcification. Using DNA microarray

technology to evaluate gene expression profiles in VSMC incubated with

1,25(OH)2D3 or paricalcitol, it was shown that, though most of the expression profile was similar, paricalcitol activates and deactivates different genes than

1,25(OH)2D3. These differences are not explained by dissimilar doses; thus, in an

experimental model of active vascular calcification induced by uremia and high

dietary P, it was shown that comparable doses of 1,25(OH)2D3, paricalcitol and doxercalciferol have significant differences in mRNA expression of Cbfα1 (Runx2) and

osteocalcin in aortic tissues, favoring paricalcitol [201, 206]. Paricalcitol, unlike

1,25(OH)2D3, did not increase the expression of transcription factor Cbfα1, which

activates one of the signaling pathways for transformation of VSMC into osteoblast-like cells [201, 206, 207]. It has also been shown that paricalcitol prevents the

activation of the P-induced Wnt/β-catenin pathway, and also reduces calcification

by downregulating the expression of BMP-2 [221, 224]. It is noteworthy that the

risk of calciphylaxis was recently reported to be increased in patients treated with

calcitriol but not in patients treated with selective vitamin D analogues such as paricalcitol or doxercalciferol [225]. Finally, the combination of nutritional vitamin D

supplementation and paricalcitol, at doses ineffective to suppress PTH when given

alone, prevented the increases in parathyroid, renal and/or macrophage TACE

expression induced by five sixths nephrectomy, thereby markedly reducing parathyroid gland enlargement, proteinuria and aortic calcification [25].

Different VDR agonists also exhibit differential effects on endothelial function

and aortic gene expression in five sixths nephrectomized rats, with alfacalcidol

exhibiting less of an effect [226]. In patients with stage 3–4 CKD, paricalcitol has

been shown to improve endothelium-dependent vasodilation [227], although these

results have not been confirmed in patients with type II diabetes and CKD [228]. On

the other hand, despite vitamin D deficiency seems to be a risk factor for arterial

hypertension, vitamin D supplementation in hypertensive patients with low circulating 25(OH)D levels had no significant effect on blood pressure and several CV risk

factors, but it was associated with a significant increase in triglycerides in a recent

randomized clinical trial [229]. In contrast to the widely described inverse association between circulating 25(OH)D levels and hypertension risk, calcitriol levels

have been recently associated positively with a higher risk of hypertension [230].

Reduction in myocardial VDR expression in rats with renal failure has also been

related to myocardial remodeling and an increase in arrhythmogenesis, being

reverted by paricalcitol by restoring myocardial VDR levels and prolonging action

potentials [231]. VDR activation by different VDR analogs has also been shown to

distinctly affect left ventricular hypertrophy, and paricalcitol was the only VDR activator which showed a relevant beneficial effect in the reduction of myocardial fibrosis, a key factor in the myocardial dysfunction in CKD patients [232]. Nevertheless,

these apparently positive results are not uniform in all studies [233–235], despite it

is now known that VDR may be a negative regulator of the TGF-β/Smad signaling,

influences the regulation of T cells and inflammatory cytokines and may ameliorate

epithelial-to-mesenchymal transition in different models [236, 237]. Many other

studies have also shown positive effects of VDR activation on myocardial structure,


Vitamin D Receptor and Interaction with DNA


left ventricular function or cardiovascular events, including dialysis and pre-dialysis

patients [44, 235, 238–241]. However, two prospective RCT’s in CKD patients

using paricalcitol did not show a significant benefit in their predefined outcomes of

left ventricular structure measured by cardiac magnetic resonance and LV function

[242, 243], although some positive results (decrease in cardiovascular-related hospitalizations, left atrial volume index, attenuation of BNP rise) were described in secondary or post-hoc analysis [242, 244].

Finally, VS-105, a novel VDR activator, has been recently shown to improve

cardiac function in five sixths nephrectomized rats [245]. A thorough review of the

different VDR activators that are being developed in different areas, including CKD,

heart disease or oncology, is completely beyond the scope of this chapter [73].

However, the current available information underlines the increasing importance of

the vitamin D/VDR pleiotropic multifunctional axis, both in health and disease.

Nevertheless, it is important to recognize that RCTs are required to confirm all the

cardiovascular or survival alleged benefits of the old and these new compounds [34,

44, 219, 220].


1. Razin A. CpG methylation, chromatin structure and gene silencing-a three-way connection.

EMBO J. 1998;17:4905–8.

2. Carlberg C. Target genes of vitamin D: spatio-temporal interaction of chromatin, VDR, and

response elements. In: Vitamin D. 3rd ed. Oxford, UK: Elsevier; 2011. p. 211–26.

3. Evans RM, Mangelsdorf DJ. Nuclear receptors, RXR, and the Big Bang. Cell. 2014;157:


4. Maglich JM, Sluder A, Guan X, et al. Comparison of complete nuclear receptor sets from the

human, caenorhabditis elegans and drosophila genomes. Genome Biol. 2001;2:RESEARCH0029.

5. Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the nuclear

receptor superfamily. Cell. 1999;97:161–63.

6. Pike JW, Meyer MB, Lee SM. The vitamin D receptor: biochemical, molecular, biological

and genomic era investigations. In: Vitamin D. 3rd ed. Oxford, UK: Elsevier; 2011. p. 97–135.

7. Robinson-Rechavi M, Carpentier AS, Duffraisse M, et al. How many nuclear hormone receptors are there in the human genome? Trends Genet. 2001;17:554–6.

8. Helsen C, Claessens F. Looking at nuclear receptors from a new angle. Mol Cell Endocrinol.


9. Norman AW. The mode of action of vitamin D. Biol Rev Camb Philos Soc. 1968;43:97–137.

10. Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biological active vitamin D

metabolite. Nature. 1970;228:764–6.

11. Wang Y, Zhu J, DeLuca HF. The vitamin D receptor in the proximal renal tubule is a key

regulator of serum 1alpha,25-dihydroxyvitamin D(3). Am J Physiol Endocrinol Metab.


12. Rojas-Rivera J, De La Piedra C, Ramos A, et al. The expanding spectrum of biological

actions of vitamin D. Nephrol Dial Transplant. 2010;25:2850–65.

13. Owen TA, Aronow MS, Barone LM, et al. Pleiotropic effects of vitamin D on osteoblast gene

expression are related to the proliferative and differentiated state of the bone cell phenotype:

dependency upon basal levels of gene expression, duration of exposure, and bone matrix

competency in norma. Endocrinology. 1991;128:1496–504.


J. Bover et al.

14. Haussler MR, Haussler CA, Whitfield GK, et al. The nuclear vitamin D receptor controls the

expression of genes encoding factors which feed the “Fountain of Youth” to mediate healthful

aging. J Steroid Biochem Mol Biol. 2010;121:88–97.

15. Bar-Shavit Z, Teitelbaum SL, Reitsma P, et al. Induction of monocytic differentiation and

bone resorption by 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A. 1983;80:


16. Haussler MR, Whitfield GK, Haussler CA, Hsieh J-C, Jurutka PW. Nuclear vitamin D receptor: natural lingands, molecular structure-function, and transcriptional control of viral genes.

In: Vitamin D. 3rd ed. Oxford, UK: Elsevier; 2011. pp.137–70.

17. Liu W, Yu WR, Carling T, et al. Regulation of gp330/megalin expression by vitamins A and

D. Eur J Clin Invest. 1998;28:100–7.

18. Canaff L, Hendy GN. Human calcium-sensing receptor gene. Vitamin D response elements

in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D. J

Biol Chem. 2002;277:30337–50.

19. Lau WL, Leaf EM, Hu MC, et al. Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int. 2012;82:1261–70.

20. Hesse M, Frohlich LF, Zeitz U, et al. Ablation of vitamin D signaling rescues bone, mineral,

and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol. 2007;26:75–84.

21. Renkema KY, Alexander RT, Bindels RJ, et al. Calcium and phosphate homeostasis: concerted interplay of new regulators. Ann Med. 2008;40:82–91.

22. Cohen-Lahav M, Shany S, Tobvin D, et al. Vitamin D decreases NFkappaB activity by

increasing IkappaBalpha levels. Nephrol Dial Transplant. 2006;21:889–97.

23. Moreno J, Krishnan AV, Swami S, et al. Regulation of prostaglandin metabolism by calcitriol

attenuates growth stimulation in prostate cancer cells. Cancer Res. 2005;65:7917–25.

24. Keisala T, Minasyan A, Lou Y-R, et al. Premature aging in vitamin D receptor mutant mice.

J Steroid Biochem Mol Biol. 2009;115:91–7.

25. Dusso A, Arcidiacono MV, Yang J, et al. Vitamin D inhibition of TACE and prevention of

renal osteodystrophy and cardiovascular mortality. J Steroid Biochem Mol Biol. 2010;121:


26. Morgado-Pascual JL, Rayego-Mateos S, Valdivielso JM, et al. Paricalcitol inhibits

aldosterone-induced proinflammatory factors by modulating epidermal growth factor receptor pathway in cultured tubular epithelial cells. Biomed Res Int. 2015;2015:783538.

27. Husain K, Hernandez W, Ansari RA, et al. Inflammation, oxidative stress and renin angiotensin system in atherosclerosis. World J Biol Chem. 2015;6:209–17.

28. Kuro-o M. Klotho and aging. Biochim Biophys Acta. 2009;1790:1049–58.

29. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a

syndrome resembling ageing. Nature. 1997;390:45–51.

30. Hu MC, Kuro-o M, Moe OW. Klotho and chronic kidney disease. Contrib Nephrol. 2013;180:


31. Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic

kidney disease. J Am Soc Nephrol. 2010;22:124–36.

32. Richards JB, Valdes AM, Gardner JP, et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. Am J Clin Nutr. 2007;86:1420–5.

33. Feldman D, Krishnan AV, Swami S, et al. The role of vitamin D in reducing cancer risk and

progression. Nat Rev Cancer. 2014;14:342–57.

34. Cozzolino M, Bover J, Vervloet M, Brandenburg V. A multidisciplinary review of the science

of vitamin D receptor activation. Kidney Int Suppl. 2011;1:107–10.

35. Omdahl JL, Morris HA, May BK. Hydroxylase enzymes of the vitamin D pathway: expression, function, and regulation. Annu Rev Nutr. 2002;22:139–66.

36. Adams JS, Singer FR, Gacad MA, et al. Isolation and structural identification of

1,25-dihydroxyvitamin D3 produced by cultured alveolar macrophages in sarcoidosis. J Clin

Endocrinol Metab. 1985;60:960–6.


Vitamin D Receptor and Interaction with DNA


37. Dusso AS, Tokumoto M. Defective renal maintenance of the vitamin D endocrine system

impairs vitamin D renoprotection: a downward spiral in kidney disease. Kidney Int.


38. Holick MF. Vitamin D: evolutionary, physiological and health perspectives. Curr Drug

Targets. 2011;12:4–18.

39. Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and

D take centre stage. Nat Rev Immunol. 2008;8:685–98.

40. Chun RF, Liu PT, Modlin RL, et al. Impact of vitamin D on immune function: lessons learned

from genome-wide analysis. Front Physiol. 2014;5:151.

41. White JH. Vitamin D, signaling, infectious diseases, and regulation of innate immunity.

Infect Immun. 2008;76:3837–43.

42. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human

antimicrobial response. Science. 2006;311:1770–3.

43. Santoro D, Lucisano S, Gagliostro G, et al. Vitamin D receptor polymorphism in chronic

kidney disease patients with complicated cardiovascular disease. J Ren Nutr. 2015;25:


44. Pilz S, Tomaschitz A, Drechsler C, et al. Vitamin D deficiency and heart disease. Kidney Int

Suppl. 2011;1:111–5.

45. Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator

of the renin-angiotensin system. J Clin Invest. 2002;110:229–38.

46. Arcidiacono MV, Cozzolino M, Spiegel N, et al. Activator protein 2alpha mediates parathyroid TGF-alpha self-induction in secondary hyperparathyroidism. J Am Soc Nephrol.


47. Staab CA, Maser E. 11beta-Hydroxysteroid dehydrogenase type 1 is an important regulator

at the interface of obesity and inflammation. J Steroid Biochem Mol Biol. 2010;119:56–72.

48. Cozzolino M, Lu Y, Finch J, et al. p21WAF1 and TGF-alpha mediate parathyroid growth

arrest by vitamin D and high calcium. Kidney Int. 2001;60:2109–17.

49. Melenhorst WB, Visser L, Timmer A, et al. ADAM17 upregulation in human renal disease: a

role in modulating TGF-alpha availability? Am J Physiol Renal Physiol. 2009;297:F781–90.

50. Donate-Correa J, Dominguez-Pimentel V, Mendez-Perez ML, et al. Selective vitamin D

receptor activation as anti-inflammatory target in chronic kidney disease. Mediators Inflamm.


51. Navarro-González JF, Donate-Correa J, Méndez ML, et al. Anti-inflammatory profile of paricalcitol in hemodialysis patients: a prospective, open-label, pilot study. J Clin Pharmacol.


52. Shahnazari M, Yao W, Corr M, et al. Targeting the Wnt signaling pathway to augment bone

formation. Curr Osteoporos Rep. 2008;6:142–8.

53. Chen D, Li Y, Zhou Z, et al. HIF-1α inhibits Wnt signaling pathway by activating Sost

expression in osteoblasts. PLoS One. 2013;8:e65940.

54. London GM. Mechanisms of arterial calcifications and consequences for cardiovascular

function. Kidney Int Suppl. 2013;3:442–5.

55. Nigwekar SU, Thadhani R. Vitamin D receptor activation: cardiovascular and renal implications. Kidney Int Suppl. 2013;3:427–30.

56. Labuda M, Fujiwara TM, Ross MV, et al. Two hereditary defects related to vitamin D metabolism map to the same region of human chromosome 12q13–14. J Bone Miner Res.


57. Glorieux G, Vanholder R. Blunted response to vitamin D in uremia. Kidney Int Suppl.


58. Brumbaugh PF, Haussler MR. 1 Alpha,25-dihydroxycholecalciferol receptors in intestine.

I. Association of 1 alpha,25-dihydroxycholecalciferol with intestinal mucosa chromatin.

J Biol Chem. 1974;249:1251–7.

59. Lawson DE, Wilson PW. Intranuclear localization and receptor proteins for

1,25-dihydroxycholecalciferol in chick intestine. Biochem J. 1974;144:573–83.


J. Bover et al.

60. Brumbaugh PF, Haussler MR. Specific binding of 1alpha,25-dihydroxycholecalciferol to

nuclear components of chick intestine. J Biol Chem. 1975;250:1588–94.

61. Hsu CH, Patel SR. Uremic toxins and vitamin D metabolism. Kidney Int Suppl. 1997;62:


62. Pike JW, Haussler MR. Purification of chicken intestinal receptor for 1,25-dihydroxyvitamin

D. Proc Natl Acad Sci U S A. 1979;76:5485–9.

63. Polly P, Herdick M, Moehren U, et al. VDR-Alien: a novel, DNA-selective vitamin D(3)

receptor-corepressor partnership. FASEB J Off Publ Fed Am Soc Exp Biol. 2000;14:


64. Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. Clin Chim

Acta. 2006;371:1–12.

65. Alvarez-Hernandez D, Naves-Diaz M, Gomez-Alonso C, et al. Tissue-specific effect of VDR

gene polymorphisms on the response to calcitriol. J Nephrol. 2008;21:843–9.

66. Negri AL, Brandenburg VM. Calcitriol resistance in hemodialysis patients with secondary

hyperparathyroidism. Int Urol Nephrol. 2014;46:1145–51.

67. Marco MP, Martinez I, Amoedo ML, et al. Vitamin D receptor genotype influences parathyroid hormone and calcitriol levels in predialysis patients. Kidney Int. 1999;56:1349–53.

68. Marco MP, Martinez I, Betriu A, et al. Influence of Bsml vitamin D receptor gene polymorphism on the response to a single bolus of calcitrol in hemodialysis patients. Clin Nephrol.


69. Borras M, Torregrossa V, Oliveras A, et al. BB genotype of the vitamin D receptor gene

polymorphism postpones parathyroidectomy in hemodialysis patients. J Nephrol. 2003;16:


70. Bover J, Bosch RJ. Vitamin D receptor polymorphisms as a determinant of bone mass and

PTH secretion: from facts to controversies. Nephrol Dial Transplant. 1999;14:1066–8.

71. Alvarez-Hernandez D, Naves M, Santamaria I, et al. Response of parathyroid glands to calcitriol in culture: is this response mediated by the genetic polymorphisms in vitamin D receptor? Kidney Int Suppl. 2003;63:S19–22.

72. Green S, Walter P, Kumar V, et al. Human oestrogen receptor cDNA: sequence, expression

and homology to v-erb-A. Nature. 1986;320:134–9.

73. Natacha Rochel DM. Structural basis for ligand activity in VDR. In: Vitamin D. 3rd ed.

Oxford, UK: Elsevier; 2011. p. 171191.

74. Hsu CH, Patel S, Young EW, et al. Production and degradation of calcitriol in renal failure

rats. Am J Physiol. 1987;253:F1015–9.

75. Cyert MS. Regulation of nuclear localization during signaling. J Biol Chem. 2001;276:20805–8.

76. Umesono K, Murakami KK, Thompson CC, et al. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell. 1991;65:1255–

66; 76b. Dowd DR, MacDonald PN. Coregulators of VDR-mediated gene expression. In:

Vitamin D. 3rd ed. Elsevier; 2011, p. 193–210.

77. Thompson PD, Jurutka PW, Haussler CA, et al. Heterodimeric DNA binding by the vitamin

D receptor and retinoid X receptors is enhanced by 1,25-dihydroxyvitamin D3 and inhibited

by 9-cis-retinoic acid. Evidence for allosteric receptor interactions. J Biol Chem.


78. Lemon BD, Fondell JD, Freedman LP. Retinoid X receptor: vitamin D3 receptor heterodimers promote stable preinitiation complex formation and direct 1,25-dihydroxyvitamin

D3-dependent cell-free transcription. Mol Cell Biol. 1997;17:1923–37.

79. Greschik H, Moras D. Structure-activity relationship of nuclear receptor-ligand interactions.

Curr Top Med Chem. 2003;3:1573–99.

80. Rochel N, Wurtz JM, Mitschler A, et al. The crystal structure of the nuclear receptor for

vitamin D bound to its natural ligand. Mol Cell. 2000;5:173–9.

81. Yamamoto K, Anami Y, Itoh T. Development of vitamin D analogs modulating the pocket

structure of vitamin D receptor. Curr Top Med Chem. 2014;14:2378–87.

82. Moras D, Gronemeyer H. The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol. 1998;10:384–91.


Vitamin D Receptor and Interaction with DNA


83. Molnar F, Perakyla M, Carlberg C. Vitamin D receptor agonists specifically modulate the

volume of the ligand-binding pocket. J Biol Chem. 2006;281:10516–26.

84. Carlberg C, Molnar F. Vitamin D receptor signaling and its therapeutic implications: genomewide and structural view. Can J Physiol Pharmacol. 2015;93:311–8.

85. Kerner SA, Scott RA, Pike JW. Sequence elements in the human osteocalcin gene confer

basal activation and inducible response to hormonal vitamin D3. Proc Natl Acad Sci U S A.


86. Diane R, Dowd PNM. Corregulators of VDR-mediated gene expression. In: Vitamin D.

3rd ed. Oxford, UK: Elsevier; 2011. p. 193–209.

87. Toell A, Polly P, Carlberg C. All natural DR3-type vitamin D response elements show a similar functionality in vitro. Biochem J. 2000;352(Pt 2):301–9.

88. Van den Bemd G-JCM, Jhamai M, Staal A, et al. A central dinucleotide within vitamin D

response elements modulates DNA binding and transactivation by the vitamin D receptor in

cellular response to natural and synthetic ligands. J Biol Chem. 2002;277:14539–46.

89. Staal A, van Wijnen AJ, Birkenhager JC, et al. Distinct conformations of vitamin D receptor/retinoid

X receptor-alpha heterodimers are specified by dinucleotide differences in the vitamin D-responsive

elements of the osteocalcin and osteopontin genes. Mol Endocrinol. 1996;10:1444–56.

90. White JH. Profiling 1,25-dihydroxyvitamin D3-regulated gene expression by microarray

analysis. J Steroid Biochem Mol Biol. 2004;89–90:239–44.

91. Kim M-S, Kondo T, Takada I, et al. DNA demethylation in hormone-induced transcriptional

derepression. Nature. 2009;461:1007–12.

92. Llach F, Bover J. Renal osteodystrophies. In: Brenner BM, editor. The kidney. 6th ed.

Philadelphia: WB Saunders Company; 2000. p. 2013–186.

93. Mackey SL, Heymont JL, Kronenberg HM, et al. Vitamin D receptor binding to the negative

human parathyroid hormone vitamin D response element does not require the retinoid x

receptor. Mol Endocrinol. 1996;10:298–305.

94. Okazaki T, Nishimori S, Ogata E, et al. Vitamin D-dependent recruitment of DNA-PK to the

chromatinized negative vitamin D response element in the PTHrP gene is required for gene

repression by vitamin D. Biochem Biophys Res Commun. 2003;304:632–7.

95. Chen LC, Tarone R, Huynh M, et al. High dietary retinoic acid inhibits tumor promotion and

malignant conversion in a two-stage skin carcinogenesis protocol using 7,12-dimethylbenz[a]

anthracene as the initiator and mezerein as the tumor promoter in female SENCAR mice.

Cancer Lett. 1995;95:113–8.

96. Meyer MB, Benkusky NA, Lee C-H, et al. Genomic determinants of gene regulation by

1,25-dihydroxyvitamin D3 during osteoblast-lineage cell differentiation. J Biol Chem.


97. Long MD, Sucheston-Campbell LE, Campbell MJ. Vitamin D receptor and RXR in the postgenomic era. J Cell Physiol. 2015;230:758–66.

98. Kozumenko A, Ohtake F, Fujiki R, Kato S. Epigenetic modifications in vitamin D receptormediated transrepression. In: Vitamin D. 3rd ed. Oxford, UK: Elsevier; 2011. p. 227–34.

99. Saccone D, Asani F, Bornman L. Regulation of the vitamin D receptor gene by environment,

genetics and epigenetics. Gene. 2015;561:171–80.

100. Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second

decade. Cell. 1995;83:835–9.

101. Dusso AS. Kidney disease and vitamin D levels: 25-hydroxyvitamin D, 1,25-dihydroxyvitamin

D, and VDR activation. Kidney Int Suppl. 2011;1:136–41.

102. McKenna NJ, Cooney AJ, DeMayo FJ, et al. Minireview: evolution of NURSA, the nuclear

receptor signaling atlas. Mol Endocrinol. 2009;23:740–6.

103. Endo I. Current topics on vitamin D. Combined therapy of anti-resorptive drug and active

vitamin D. Clin Calcium. 2015;25:433–8.

104. Molnar F. Structural considerations of vitamin D signaling. Front Physiol. 2014;5:191.

105. Ecker JR, Bickmore WA, Barroso I, et al. The ENCODE Project Consortium. An integrated

encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.


J. Bover et al.

106. Seuter S, Heikkinen S, Carlberg C. Chromatin acetylation at transcription start sites and

vitamin D receptor binding regions relates to effects of 1alpha,25-dihydroxyvitamin D3 and

histone deacetylase inhibitors on gene expression. Nucleic Acids Res. 2013;41:110–24.

107. Onate SA, Tsai SY, Tsai MJ, et al. Sequence and characterization of a coactivator for the

steroid hormone receptor superfamily. Science. 1995;270:1354–7.

108. Choi JK, Howe LJ. Histone acetylation: truth of consequences? Biochem Cell Biol.


109. Chakravarti D, LaMorte VJ, Nelson MC, et al. Role of CBP/P300 in nuclear receptor signalling. Nature. 1996;383:99–103.

110. Wang F, Marshall CB, Ikura M. Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis: structural and functional versatility in target recognition. Cell Mol Life Sci. 2013;70:


111. Oda Y, Sihlbom C, Chalkley RJ, et al. Two distinct coactivators, DRIP/mediator and SRC/

p160, are differentially involved in vitamin D receptor transactivation during keratinocyte

differentiation. Mol Endocrinol. 2003;17:2329–39.

112. Varshney S, Bhadada SK, Sachdeva N, et al. Methylation status of the CpG islands in vitamin

D and calcium-sensing receptor gene promoters does not explain the reduced gene expressions in parathyroid adenomas. J Clin Endocrinol Metab. 2013;98:E1631–5.

113. Rachez C, Freedman LP. Mediator complexes and transcription. Curr Opin Cell Biol.


114. Belakavadi M, Fondell JD. Role of the mediator complex in nuclear hormone receptor signaling. Rev Physiol Biochem Pharmacol. 2006;156:23–43.

115. Barry JB, Leong GM, Church WB, et al. Interactions of SKIP/NCoA-62, TFIIB, and retinoid

X receptor with vitamin D receptor helix H10 residues. J Biol Chem. 2003;278:8224–8.

116. Pathrose P, Barmina O, Chang C-Y, et al. Inhibition of 1,25-dihydroxyvitamin D3-dependent

transcription by synthetic LXXLL peptide antagonists that target the activation domains of

the vitamin D and retinoid X receptors. J Bone Miner Res. 2002;17:2196–205.

117. Wang X, Arai S, Song X, et al. Induced ncRNAs allosterically modify RNA-binding proteins

in cis to inhibit transcription. Nature. 2008;454:126–30.

118. Wang X, Song X, Glass CK, et al. The long arm of long noncoding RNAs: roles as sensors

regulating gene transcriptional programs. Cold Spring Harb Perspect Biol. 2011;3:a003756.

119. Burakov D, Crofts LA, Chang C-PB, et al. Reciprocal recruitment of DRIP/mediator and

p160 coactivator complexes in vivo by estrogen receptor. J Biol Chem. 2002;277:14359–62.

120. Issa LL, Leong GM, Sutherland RL, et al. Vitamin D analogue-specific recruitment of vitamin D receptor coactivators. J Bone Miner Res. 2002;17:879–90.

121. Mizwicki MT, Norman AW. Vitamin D sterol/VDR conformational dynamics and nongenomis actions. In: Vitamin D. 3rd ed. Oxford, UK: Elsevier; 2011. p. 271–97.

122. Nemere I, Hintze K. Novel hormone “receptors”. J Cell Biochem. 2008;103:401–7.

123. Gallieni M, Kamimura S, Ahmed A, et al. Kinetics of monocyte 1 alpha-hydroxylase in renal

failure. Am J Physiol. 1995;268:F746–53.

124. Malinen M, Saramaki A, Ropponen A, et al. Distinct HDACs regulate the transcriptional

response of human cyclin-dependent kinase inhibitor genes to trichostatin A and 1alpha,25dihydroxyvitamin D3. Nucleic Acids Res. 2008;36:121–32.

125. Dobrzynski M, Bruggeman FJ. Elongation dynamics shape bursty transcription and translation. Proc Natl Acad Sci U S A. 2009;106:2583–8.

126. Peleg S, Nguyen CV. The importance of nuclear import in protection of the vitamin D receptor from polyubiquitination and proteasome-mediated degradation. J Cell Biochem.


127. Cozzolino M, Stucchi A, Rizzo MA, et al. Vitamin D receptor activation and prevention of

arterial ageing. Nutr Metab Cardiovasc Dis. 2012;22:547–52.

128. Xu SS, Alam S, Margariti A. Epigenetics in vascular disease - therapeutic potential of new

agents. Curr Vasc Pharmacol. 2014;12:77–86.

129. Fukagawa M, Kaname S, Igarashi T, et al. Regulation of parathyroid hormone synthesis in

chronic renal failure in rats. Kidney Int. 1991;39:874–81.


Vitamin D Receptor and Interaction with DNA


130. Helvig CF, Cuerrier D, Hosfield CM, et al. Dysregulation of renal vitamin D metabolism in

the uremic rat. Kidney Int. 2010;78:463–72.

131. Hsu CH, Patel SR. Altered vitamin D metabolism and receptor interaction with the target

genes in renal failure: calcitriol receptor interaction with its target gene in renal failure. Curr

Opin Nephrol Hypertens. 1995;4:302–6.

132. Bover J, Rodriguez M, Trinidad P, et al. Factors in the development of secondary hyperparathyroidism during graded renal failure in the rat. Kidney Int. 1994;45:953–61.

133. Bover J, Jara A, Trinidad P, et al. The calcemic response to PTH in the rat: effect of elevated

PTH levels and uremia. Kidney Int. 1994;46:310–7.

134. DeFronzo RA, Alvestrand A, Smith D, et al. Insulin resistance in uremia. J Clin Invest.


135. Blum WF, Ranke MB, Kietzmann K, et al. Growth hormone resistance and inhibition of

somatomedin activity by excess of insulin-like growth factor binding protein in uraemia.

Pediatr Nephrol. 1991;5:539–44.

136. Lim K, Lu T-S, Molostvov G, et al. Vascular klotho deficiency potentiates the development

of human artery calcification and mediates resistance to fibroblast growth factor 23.

Circulation. 2012;125:2243–55.

137. Kazama JJ, Sato F, Omori K, et al. Pretreatment serum FGF-23 levels predict the efficacy of

calcitriol therapy in dialysis patients. Kidney Int. 2005;67:1120–5.

138. Vulpio C, Maresca G, Distasio E, et al. Switch from calcitriol to paricalcitol in secondary

hyperparathyroidism of hemodialysis patients: responsiveness is related to parathyroid gland

size. Hemodial Int. 2011;15:69–78.

139. Manolagas SC, Yu XP, Girasole G, et al. Vitamin D and the hematolymphopoietic tissue: a

1994 update. Semin Nephrol. 1994;14:129–43.

140. Hsu CH, Patel SR, Young EW, et al. The biological action of calcitriol in renal failure. Kidney

Int. 1994;46:605–12.

141. Fukuda N, Tanaka H, Tominaga Y, et al. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic

patients. J Clin Invest. 1993;92:1436–43.

142. Patel SR, Ke HQ, Vanholder R, et al. Inhibition of nuclear uptake of calcitriol receptor by

uremic ultrafiltrate. Kidney Int. 1994;46:129–33.

143. Walling MW, Kimberg DV, Wasserman RH, et al. Duodenal active transport of calcium and

phosphate in vitamin D-deficient rats: effects of nephrectomy, Cestrum diurnum, and

1alpha,25-dihydroxyvitamin D3. Endocrinology. 1976;98:1130–4.

144. Baker LR, Abrams L, Roe CJ, et al. 1,25(OH)2D3 administration in moderate renal failure: a

prospective double-blind trial. Kidney Int. 1989;35:661–9.

145. Toell A, Degenhardt S, Grabensee B, et al. Inhibitory effect of uremic solutions on proteinDNA-complex formation of the vitamin D receptor and other members of the nuclear receptor superfamily. J Cell Biochem. 1999;74:386–94.

146. Patel SR, Ke HQ, Vanholder R, et al. Inhibition of calcitriol receptor binding to vitamin D

response elements by uremic toxins. J Clin Invest. 1995;96:50–9.

147. Jurutka PW, Hsieh JC, MacDonald PN, et al. Phosphorylation of serine 208 in the human vitamin

D receptor. The predominant amino acid phosphorylated by casein kinase II, in vitro, and identification as a significant phosphorylation site in intact cells. J Biol Chem. 1993;268:6791–9.

148. Cake MH, DiSorbo DM, Litwack G. Effect of pyridoxal phosphate on the DNA binding site

of activated hepatic glucocorticoid receptor. J Biol Chem. 1978;253:4886–91.

149. Reinhardt TA, Horst RL. Parathyroid hormone down-regulates 1,25-dihydroxyvitamin D

receptors (VDR) and VDR messenger ribonucleic acid in vitro and blocks homologous upregulation of VDR in vivo. Endocrinology. 1990;127:942–8.

150. Chen TL, Li JM, Ye TV, et al. Hormonal responses to 1,25-dihydroxyvitamin D3 in cultured

mouse osteoblast-like cells--modulation by changes in receptor level. J Cell Physiol.


151. Hsu CH, Patel SR, Vanholder R. Mechanism of decreased intestinal calcitriol receptor concentration in renal failure. Am J Physiol. 1993;264:F662–9.


J. Bover et al.

152. Korkor AB. Reduced binding of [3H]1,25-dihydroxyvitamin D3 in the parathyroid glands of

patients with renal failure. N Engl J Med. 1987;316:1573–7.

153. Brown AJ, Dusso A, Lopez-Hilker S, et al. 1,25-(OH)2D receptors are decreased in parathyroid glands from chronically uremic dogs. Kidney Int. 1989;35:19–23.

154. Merke J, Hugel U, Zlotkowski A, et al. Diminished parathyroid 1,25(OH)2D3 receptors in

experimental uremia. Kidney Int. 1987;32:350–3.

155. De Francisco ALM, Olmos JM, Martinez J. Calcitriol receptors after correction of uremia

(Abstract). In: XII international congress of nephrology, Jerusalem; 1993.

156. Hirst M, Feldman D. Regulation of 1,25(OH)2 vitamin D3 receptor content in cultured

LLC-PK1 kidney cells limits hormonal responsiveness. Biochem Biophys Res Commun.


157. Szabo A, Merke J, Thomasset M, et al. No decrease of 1,25(OH)2D3 receptors and duodenal

calbindin-D9k in uraemic rats. Eur J Clin Invest. 1991;21:521–6.

158. Szabó A, Ritz E, Schmidt-Gayk H, et al. Abnormal expression and regulation of vitamin D

receptor in experimental uremia. Nephron. 1996;73:619–28.

159. Naveh-Many T, Marx R, Keshet E, et al. Regulation of 1,25-dihydroxyvitamin D3 receptor

gene expression by 1,25-dihydroxyvitamin D3 in the parathyroid in vivo. J Clin Invest.


160. Costa EM, Feldman D. Homologous up-regulation of the 1,25 (OH)2 vitamin D3 receptor in

rats. Biochem Biophys Res Commun. 1986;137:742–7.

161. Patel SR, Ke HQ, Hsu CH. Regulation of calcitriol receptor and its mRNA in normal and

renal failure rats. Kidney Int. 1994;45:1020–7.

162. Lopez I, Aguilera-Tejero E, Mendoza FJ, et al. Calcimimetic R-568 decreases extraosseous

calcifications in uremic rats treated with calcitriol. J Am Soc Nephrol. 2006;17:795–804.

163. Canalejo R, Canalejo A, Martinez-Moreno JM, et al. FGF23 fails to inhibit uremic parathyroid glands. J Am Soc Nephrol. 2010;21:1125–35.

164. Brown AJ, Zhong M, Finch J, et al. The roles of calcium and 1,25-dihydroxyvitamin D3 in

the regulation of vitamin D receptor expression by rat parathyroid glands. Endocrinology.


165. Denda M, Finch J, Brown AJ, et al. 1,25-dihydroxyvitamin D3 and 22-oxacalcitriol prevent

the decrease in vitamin D receptor content in the parathyroid glands of uremic rats. Kidney

Int. 1996;50:34–9.

166. Wiese RJ, Uhland-Smith A, Ross TK, et al. Up-regulation of the vitamin D receptor in

response to 1,25-dihydroxyvitamin D3 results from ligand-induced stabilization. J Biol

Chem. 1992;267:20082–6.

167. Brown AJ, Berkoben M, Ritter CS, et al. Binding and metabolism of 1,25-dihydroxyvitamin

D3 in cultured bovine parathyroid cells. Endocrinology. 1992;130:276–81.

168. Goff JP, Reinhardt TA, Beckman MJ, et al. Contrasting effects of exogenous

1,25-dihydroxyvitamin D [1,25-(OH)2D] versus endogenous 1,25-(OH)2D, induced by

dietary calcium restriction, on vitamin D receptors. Endocrinology. 1990;126:1031–5.

169. Garfia B, Canadillas S, Canalejo A, et al. Regulation of parathyroid vitamin D receptor

expression by extracellular calcium. J Am Soc Nephrol. 2002;13:2945–52.

170. Mendoza FJ, Lopez I, Canalejo R, et al. Direct upregulation of parathyroid calcium-sensing

receptor and vitamin D receptor by calcimimetics in uremic rats. Am J Physiol Renal Physiol.


171. Russell J, Bar A, Sherwood LM, et al. Interaction between calcium and 1,25-dihydroxyvitamin

D3 in the regulation of preproparathyroid hormone and vitamin D receptor messenger ribonucleic acid in avian parathyroids. Endocrinology. 1993;132:2639–44.

172. Sela-Brown A, Russell J, Koszewski NJ, et al. Calreticulin inhibits vitamin D′s action on the

PTH gene in vitro and may prevent vitamin D′s effect in vivo in hypocalcemic rats. Mol

Endocrinol. 1998;12:1193–200.

173. Carrillo-Lopez N, Alvarez-Hernandez D, Gonzalez-Suarez I, et al. Simultaneous changes in

the calcium-sensing receptor and the vitamin D receptor under the influence of calcium and

calcitriol. Nephrol Dial Transplant. 2008;23:3479–84.

Tài liệu bạn tìm kiếm đã sẵn sàng tải về

8 Therapeutic Implications: Selective Vitamin D Receptor Activators in CKD

Tải bản đầy đủ ngay(0 tr)