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1.
J Steroid Biochem Mol Biol ; 195: 105484, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31574299

RESUMO

Vitamin D deficiency has been associated with increased risk for aggressive prostate cancer (PCa). Prostate epithelium has a unique metabolism compared to other tissues. Normal prostate exhibits low levels of mitochondrial respiration and there is a metabolic switch to increased oxidative phosphorylation in PCa. 25-hydroxyvitamin D (25(OH)D) is the major circulating form of vitamin D and is used clinically to determine vitamin D status. Activation of 25(OH)D to the transcriptionally active form, 1,25(OH)2D occurs via a reduction-oxidation (redox) reaction within the mitochondria that is catalyzed by the P450 enzyme, CYP27B1. We sought to determine if hydroxylation of 25(OH)D by CYP27B1 contributes to non-genomic activity of vitamin D by altering the redox-dependent state of the mitochondria in benign prostate epithelial cells. Exposure to 25(OH)D produced a transient pro-oxidant effect and change in mitochondrial membrane potential that was dependent on CYP27B1. Extended exposure ultimately suppressed mitochondrial respiration, consistent with a protective effect of 25(OH)D in supporting benign prostate metabolism. To model physiologically relevant changes in vitamin D, cells were cultured in constant 25(OH)D then changed to high or deficient concentrations. This model also incurred a biphasic effect with a pro-oxidant shift after short exposure followed by decreased respiration after 16 h. Several genes involved in redox cycling and Mitochondrial Health were regulated by 25(OH)D in these cells. These results indicate a secondary non-genomic mechanism for vitamin D to contribute to prostate cell health by supporting normal mitochondrial respiration.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Mitocôndrias/efeitos dos fármacos , Próstata/citologia , Próstata/metabolismo , Vitamina D/farmacologia , Vitaminas/farmacologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Genômica , Humanos , Hidroxilação/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , RNA Interferente Pequeno/genética , Receptores de Calcitriol/genética
2.
J Diabetes Res ; 2019: 8289741, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583252

RESUMO

Objective: To investigate the effect of single nucleotide polymorphisms (SNPs) of the key genes in vitamin D metabolic pathway on the serum 25(OH)D level after long-term vitamin D3 supplementation and provide a theoretical basis for rational vitamin D3 supplementation in diabetic patients with different genetic backgrounds. Methods: Patients with type 2 diabetes (T2DM) who met the inclusive criteria were given 800 IU of vitamin D3 daily for 30 consecutive months. Serum 25(OH)D levels was measured at enrollment and every 6 months after enrollment. The average value of four-time measurements represented individual serum 25(OH)D level during vitamin D3 supplementation. Multiplex TaqMan genotyping was used to determine the distribution of eight candidate SNPs in genes of DHCR7, CYP2R1, CYP27B1, CYP24A1, and VDR, which are key genes in the vitamin D metabolic pathway, in diabetic patients. Results: At baseline, the average serum 25(OH)D level was 22.71 ± 6.87 ng/mL, and 17.9% of patients had a ≥30 ng/mL level. During supplementation, the level of 25(OH)D increased significantly at each time point, and the average 25(OH)D level increased to 30.61 ± 5.04 ng/mL; however, there were 44.6% of patients whose serum 25(OH)D levels were still below 30 ng/mL. In the patients with CYP27B1 (rs10877012) G/T genotype, 71.79% achieved sufficient level of 25(OH)D, which was significantly higher than the other two genotypes (P < 0.05). Compared with those with T/T genotype, the RR of the patients with rs10877012 for <30 ng/mL level was 0.544 (95% CI: 0.291-0.917), and the RR after adjusting age and outdoor activity was 0.560 (95% CI: 0.292-0.970). Conclusion: The serum 25(OH)D level in patients with diabetes mellitus after long-term vitamin D3 supplementation is associated with CYP27B1 polymorphism. Patients with rs10877012 G/T allele have a better response to vitamin D3 supplementation. Trial Registration: This trial is registered with ChiCTR-IPC-17012657.


Assuntos
Colecalciferol/uso terapêutico , Diabetes Mellitus Tipo 2/genética , Suplementos Nutricionais , Predisposição Genética para Doença , Deficiência de Vitamina D/genética , Vitamina D/análogos & derivados , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Idoso , Colecalciferol/administração & dosagem , Colestanotriol 26-Mono-Oxigenase/genética , Família 2 do Citocromo P450/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D3 24-Hidroxilase/genética
3.
Arch Virol ; 164(12): 2909-2918, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31520221

RESUMO

CYP27A1, CYP2R1 and CYP27B1 hydroxylases are involved in the synthesis of 1, 25-hydroxyvitamin D3, which plays a role in the immune regulation and pathogenesis of hepatitis C virus (HCV) infection. The aim of the present study was to investigate the relationships between polymorphisms in vitamin D pathway genes and HCV infection outcomes in a Chinese population. Nine single-nucleotide polymorphisms (SNPs) of CYP27A1, CYP2R1 and CYP27B1 were genotyped in a high-risk Chinese population. The distributions of these SNPs were compared among groups with different outcomes of HCV infection, including 863 cases of persistent HCV infection, 524 cases of spontaneous clearance, and 1079 uninfected controls. The results showed that the CYP2R1 rs12794714-G, rs10741657-A, rs1562902-C, and rs10766197-G alleles were significantly associated with increased susceptibility to HCV infection (all PFDR < 0.05, in additive/dominant models), and the combined effect of the four unfavorable alleles was related to an elevated risk of HCV infection in a locus-dosage manner (Ptrend = 0.008). Moreover, haplotype analysis suggested that, compared with the most frequent haplotype (Ars12794714Grs10741657Trs1562902Ars10766197), the haplotype containing four unfavorable alleles, GACG, was associated with a higher risk of HCV infection. The results of our study suggest that genetic variants in CYP2R1 may be biomarkers for predicting the susceptibility to HCV infection in the Chinese population.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Colestanotriol 26-Mono-Oxigenase/genética , Família 2 do Citocromo P450/genética , Hepatite C/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Casos e Controles , China , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Hepatite C/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Vitamina D/metabolismo
4.
J Steroid Biochem Mol Biol ; 195: 105449, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31470109

RESUMO

The skin is a unique site in the human body that has the capacity to synthesize the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), from 7-dehydrocholesterol (7DHC) upon UV irradiation. Keratinocytes express both 25-hydroxylase (CYP27A1 and CYP2R1) and 1α-hydroxylase (CYP27B1), critical enzymes involved in active vitamin D synthesis. Here, we investigated the effect of skin-derived 1α,25(OH)2D3, synthesized purely within the keratinocytes, on MMP-1 expression. Treatment of human epidermal keratinocytes with 1α,25(OH)2D3, but not 7DHC or 25OHD3, significantly increased MMP-1 expression. UV irradiation increases 1α,25(OH)2D3 levels, and ketoconazole inhibits UV-induced production of 1α,25(OH)2D3. Upregulation of MMP-1 by UV was reversed by inhibition of 1α,25(OH)2D3 synthesis using ketoconazole or CYP27B1 siRNA. In keratinocytes, 7DHC is a substrate for both cholesterol and 1α,25(OH)2D3 synthesis. We demonstrated that UV irradiation leads to decreased expression of DHCR7 (7-dehydrocholesterol reductase), the enzyme that converts 7DHC to cholesterol. Inhibition of DHCR7 with its inhibitor BM15766 decreased cholesterol synthesis and increased UV-induced MMP-1 expression, which was attenuated by ketoconazole. These findings suggest that UV-induced reduction of DHCR7 leads to a decrease in cholesterol synthesis, thereby increasing 7DHC availability for 1α,25(OH)2D3 production, which enhances MMP-1 expression. Finally, UV irradiation in human skin in vivo significantly increased CYP27B1 mRNA and decreased DHCR7 mRNA expression. Taken together, we demonstrate here that skin-derived 1α,25(OH)2D3 significantly increases MMP-1 expression in human keratinocytes, a previously unappreciated function of 1α,25(OH)2D3. Moreover, UV irradiation upregulates the enzyme CYP27B1, which leads to 1α,25(OH)2D3 synthesis, but downregulates the cholesterol-producing enzyme DHCR7, both of which collectively lead to increased MMP-1 expression in human keratinocytes. This pathway may be exploited to develop a novel cutaneous anti-aging agent that blocks local cutaneous 1α,25(OH)2D3 synthesis.


Assuntos
Desidrocolesteróis/metabolismo , Queratinócitos/efeitos da radiação , Metaloproteinase 1 da Matriz/metabolismo , Pele/efeitos da radiação , Raios Ultravioleta , Vitamina D/análogos & derivados , Vitaminas/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Adulto , Células Cultivadas , Humanos , Queratinócitos/metabolismo , Pessoa de Meia-Idade , Pele/metabolismo , Vitamina D/metabolismo
5.
J Clin Lab Anal ; 33(6): e22898, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30993743

RESUMO

BACKGROUND: The circulating concentration of 25(OH)D is widely applied to indicate the vitamin D status, as the directly metabolic genes of 25(OH)D, CYP2R1, and CYP27B1 are associated with the concentration of 25(OH)D. However, the contributions of allelic transmission disequilibrium of single nucleotide polymorphisms (SNPs) in these genes to vitamin D deficiency remain unclear. We aimed at investigating the family-based association between SNPs of CYP2R1 and CYP27B1 and vitamin D deficiency. METHOD: First, SNPs selected in family-based study were screened by a pilot case-control study. Second, allelic transmissions of the selected SNPs were investigated with family-based study (n = 880). Finally, associations between selected SNPs and the concentration of 25(OH)D were verified in siblings (n = 120). RESULTS: The results of the pilot case-control study indicated that both CT and TT genotypes of rs4646536 in CYP27B1 could increase the susceptibility of vitamin D deficiency when compared with CC genotype. The adjusted ORs were 2.846 (95%CI 1.312-6.174, P = 0.008) and 2.609 (95%CI 1.197-5.687, P = 0.016), respectively. Furthermore, the results of family-based association test suggested that there was transmission disequilibrium for allele T of rs4646536 in vitamin D deficiency families. In addition, the concentration of 25(OH)D3 for CC genotype was higher than CT genotype between siblings (P = 0.016). CONCLUSIONS: Transmission disequilibrium of allele T of rs4646536 is associated with vitamin D deficiency.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Polimorfismo de Nucleotídeo Único , Deficiência de Vitamina D/genética , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Calcifediol/sangue , Calcifediol/genética , Estudos de Casos e Controles , Colestanotriol 26-Mono-Oxigenase/genética , Família 2 do Citocromo P450/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Projetos Piloto , Adulto Jovem
6.
Gynecol Endocrinol ; 35(9): 772-776, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30887870

RESUMO

Turner syndrome (TS) is a common genetic disorder. TS-phenotype includes short stature, gonadal dysgenesis, cardiac and kidney malformations, low bone mineral density (low-BMD) and thyroiditis. TS-phenotype varies from patient to patient and the cause is not clear, the genomic background may be an important contributor for this variability. Our aim was to identify the association of specific single nucleotide variants in the PTPN22, VDR, KL, and CYP27B1 genes and vitamin D-metabolism, heart malformation, renal malformation, thyroiditis, and low-BMD in 61 Mexican TS-patients. DNA samples were genotyped for SNVs: rs7975232 (VDR), rs9536282 (KL), rs4646536 (CYP27B1), and rs1599971 (PTPN22) using the KASP assay. Chi-square test under a recessive model and multifactorial dimensionality reduction method were used for analysis. We found a significant association between renal malformation and the rs9536282 (KL) variant and between rs4646536 (CYP27B1) and low-BMD, these variants may have modest effects on these characteristics but contribute to the variability of the TS phenotype. In addition, we identified gene-gene interactions between variants in genes KL, CYP27B1 and VDR related to vitamin D-metabolism and low-BMD in TS-patients. Our results support the idea that the genetic background of TS-patients contributes to the clinical variability seen in them.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Doenças Ósseas Metabólicas/genética , Glucuronidase/genética , Receptores de Calcitriol/genética , Síndrome de Turner/genética , Anormalidades Urogenitais/genética , Adolescente , Adulto , Densidade Óssea/genética , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Epistasia Genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Lactente , Rim/anormalidades , Redes e Vias Metabólicas/genética , México/epidemiologia , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Receptores de Calcitriol/metabolismo , Síndrome de Turner/complicações , Síndrome de Turner/epidemiologia , Anormalidades Urogenitais/complicações , Anormalidades Urogenitais/epidemiologia , Vitamina D/metabolismo , Adulto Jovem
7.
J Neuroimmunol ; 330: 123-129, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875612

RESUMO

In this study, we analysed the association of rs703842 in CYP27B1 gene with multiple sclerosis (MS) risk and disability progression in a group of 496 MS patients and 521 controls. For the first time in Central European Slovak population, we found the rs703842 allele C to be protective factor against MS development (p = 1.09 × 10-5). Moreover, the risky genotypes TT and TC were showed to be associated with an increased MS risk, and this was aggravated by the homozygous carriage of the HLA-DRB1*15:01 allele (OR = 2.82 vs. 4.86, p < .0001). No association of rs703842 with MS disability progression or calcidiol serum level was found.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Alelos , Predisposição Genética para Doença/genética , Variação Genética/genética , Cadeias HLA-DRB1/genética , Esclerose Múltipla/genética , Adulto , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/epidemiologia , Eslováquia/epidemiologia
8.
Osteoporos Int ; 30(2): 481-489, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30382318

RESUMO

Pseudovitamin D-deficiency rickets is a rare disease which is caused by CYP27B1. In this study, we identified 9 mutations in 7 PDDR patients. In addition, we observed the response to long-term treatment of calcitriol in 15 Chinese patients with PDDR, which showed that the biochemical abnormalities had been corrected satisfactorily after 1-year treatment. INTRODUCTION: Pseudovitamin D-deficiency rickets is a rare autosomal recessive disorder resulting from a defect in 25-hydroxyvitamin D 1α-hydroxylase, which is encoded by CYP27B1. The purpose of this study was to identify the CYP27B1 mutations and investigate the response to long-term treatment of calcitriol in Chinese patients with PDDR. METHODS: We investigated CYP27B1 mutations in seven individuals from six separate families. To investigate the response to long-term (13 years) treatment with calcitriol in PDDR patients, we additionally collected clinical data of eight families from our previous report and analyzed their biochemical parameter and radiographic changes during the treatment. RESULTS: Nine different mutations were identified: two novel missense mutations (G194R, R259L), three novel and one reported deletion mutations (c1442delA, c1504delA, c311-321del, and c. 48-60del), two novel nonsense mutations (c.85G>T, c.580G>T), and a reported insertion mutation (c1325-1332insCCCACCC). The statistical analysis revealed that parathyroid hormone (PTH) and ALP significantly decreased after 6-month and 1-year treatment with calcitriol respectively. Urine calcium was measured in all the patients without kidney stones being documented. After 6-year treatment, the radiographic abnormalities had also been improved. Two patients who had reached their final height are both with short stature (height Z-score below - 2.0). CONCLUSIONS: We identified seven novel mutations of CYP27B1 gene in seven Chinese PDDR families. Our findings revealed after 1-year treatment of active vitamin D3, PTH and ALP significantly decreased. The correction of the biochemical abnormalities had not improved the final height satisfactorily.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Colecalciferol/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/genética , Mutação , Adolescente , Fosfatase Alcalina/sangue , Estatura/efeitos dos fármacos , Hormônios e Agentes Reguladores de Cálcio/administração & dosagem , Hormônios e Agentes Reguladores de Cálcio/farmacologia , Criança , Pré-Escolar , Colecalciferol/administração & dosagem , Colecalciferol/farmacologia , Análise Mutacional de DNA/métodos , Esquema de Medicação , Raquitismo Hipofosfatêmico Familiar/sangue , Raquitismo Hipofosfatêmico Familiar/diagnóstico por imagem , Feminino , Humanos , Masculino , Hormônio Paratireóideo/sangue , Linhagem , Radiografia , Resultado do Tratamento , Adulto Jovem
9.
J Clin Res Pediatr Endocrinol ; 11(1): 34-40, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30282619

RESUMO

Objective: Vitamin D dependent rickets type 1A (VDDR1A) is an autosomal recessive disorder caused by mutations in the 1α-hydroxylase gene (CYB27B1). As it may be confused with nutritional rickets and hypophosphatemic rickets, genetic analysis is important for making a correct diagnosis. Methods: We analysed genomic DNA from 11 patients from eight different Turkish families. The patients were recruited for our studies if they presented with a diagnosis of VDDR. Results: The mean ± standard deviation age at diagnosis was 13.1±7.4 months. Seven patients had mild hypocalcemia at presentation while four patients had normal calcium concentrations. All patients underwent CYP27B1 gene analysis. The most prevalent mutation was the c.195 + 2T>G splice donor site mutation, affecting five out of 11 patients with VDDR1A. Two patients from the fourth family were compound heterozygous for c.195 + 2T>G and c.195 + 2 T>A in intron-1. Two patients, from different families, were homozygous for a previously reported duplication mutation in exon 8 (1319_1325dupCCCACCC, Phe443Profs*24). One patient had a homozygous splice site mutation in intron 7 (c.1215 + 2 T>A) and one patient had a homozygous mutation in exon 9 (c.1474 C>T). Conclusion: Intron-1 mutation was the most common mutation, as previously reported. All patients carrying that mutation were from same city of origin suggesting a "founder" or a "common ancestor" effect. VDDR1A should definitely be considered when a patient with signs of rickets has a normal 25-OHD level or when there is unresponsiveness to vitamin D treatment.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Raquitismo Hipofosfatêmico Familiar/genética , Análise de Sequência de DNA , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Linhagem , Turquia
10.
Clin Exp Immunol ; 195(2): 265-276, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30216432

RESUMO

Anti-microbial resistance increases among bacterial pathogens and new therapeutic avenues needs to be explored. Boosting innate immune mechanisms could be one attractive alternative in the defence against infectious diseases. The cholesterol-lowering drugs, statins, have been demonstrated to also affect the immune system. Here we investigate the effect of statins on the expression of the human cathelicidin anti-microbial peptide (CAMP) LL-37/hCAP-18 [encoded by the CAMP gene] and explore the underlying mechanisms in four epithelial cell lines of different origin. Simvastatin induced CAMP expression in bladder epithelial cells telomerase-immortalized uroepithelial cells (TERT-NHUCs), intestinal cells HT-29 and keratinocytes HEKa, but not in airway epithelial cells A549. Gene induction in HEKa cells was reversible by mevalonate, while this effect was independent of the cholesterol biosynthesis pathway in TERT-NHUCs. Instead, inhibition of histone deacetylases by simvastatin seems to be involved. For HT-29 cells, both mechanisms may contribute. In addition, simvastatin increased transcription of the vitamin D-activating enzyme CYP27B1 which, in turn, may activate LL-37/hCAP-18 production. Taken together, simvastatin is able to promote the expression of LL-37/hCAP-18, but cell line-specific differences in efficacy and the involved signalling pathways exist.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Peptídeos Catiônicos Antimicrobianos/biossíntese , Infecções por Escherichia coli/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Linhagem Celular , Farmacorresistência Bacteriana Múltipla , Células Epiteliais/metabolismo , Escherichia coli/imunologia , Infecções por Escherichia coli/imunologia , Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Ácido Mevalônico/metabolismo , Transdução de Sinais , Transcrição Genética/efeitos dos fármacos , Bexiga Urinária/citologia , Bexiga Urinária/metabolismo , Vitamina D/metabolismo
11.
Free Radic Biol Med ; 131: 376-381, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578920

RESUMO

Chronic kidney disease (CKD) is a worldwide public health problem with an estimated prevalence of 8.2%. This study reports glutathione deficiency, excess oxidative stress, and altered vitamin D metabolism in the kidney of mice fed a high-fat diet (HFD). The levels of GCLC and GCLM gene expression were significantly downregulated and the protein carbonylation level, a hallmark of oxidative damage, was significantly increased in the kidney of HFD-fed mice. While the levels of VD-regulatory genes 1-alpha-hydroxylase (CYP27B1), VDR, and RXRα were significantly downregulated in the kidney of mice fed a HFD, those of 24-hydroxylase (CYP24A1) were significantly elevated. In vitro, GSH deficiency per se causes excess oxidative damage (protein carbonylation), and significantly decreases the levels of VD-regulatory genes (CYP27B1, VDR, and RXRα), but increases levels of CYP24A1 in human renal proximal tubule epithelial cells (RPTEC), similar to findings in the kidney of HFD-fed diabetic mice. L-cysteine supplementation restores GSH and prevents oxidative damage in RPTEC. These studies suggest a potential role of GSH precursor in reducing excess oxidative stress and renal injury that commonly accompanies obesity/diabetes.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Diabetes Mellitus Experimental/enzimologia , Glutationa/deficiência , Receptores de Calcitriol/genética , Insuficiência Renal Crônica/enzimologia , Vitamina D3 24-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Animais , Cisteína/farmacologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Humanos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Cultura Primária de Células , Carbonilação Proteica , Receptores de Calcitriol/metabolismo , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Receptor X Retinoide alfa/genética , Receptor X Retinoide alfa/metabolismo , Transdução de Sinais , Vitamina D3 24-Hidroxilase/metabolismo
12.
J Steroid Biochem Mol Biol ; 185: 71-79, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30031146

RESUMO

We have reported that 25-hydroxyvitamin D3 [25(OH)D3] binds to vitamin D receptor and exhibits several biological functions directly in vitro. To evaluate the direct effect of 25(OH)D3 in vivo, we used Cyp27b1 knockout (KO) mice, which had no detectable plasma 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] when fed a diet containing normal Ca and vitamin D. Daily treatment with 25(OH)D3 at 250 µg kg-1 day-1 rescued rachitic phenotypes in the Cyp27b1 KO mice. Bone mineral density, female sexual cycles, and plasma levels of Ca, P, and PTH were all normalized following 25(OH)D3 administration. An elevated Cyp24a1 mRNA expression was observed in the kidneys, and plasma concentrations of Cyp24a1-dependent metabolites of 25(OH)D3 were increased. To our surprise, 1,25(OH)2D3 was detected at a normal level in the plasma of Cyp27b1 KO mice. The F1 to F4 generations of Cyp27b1 KO mice fed 25(OH)D3 showed normal growth, normal plasma levels of Ca, P, and parathyroid hormone, and normal bone mineral density. The curative effect of 25(OH)D3 was considered to depend on the de novo synthesis of 1,25(OH)2D3 in the Cyp27b1 KO mice. This suggests that another enzyme than Cyp27b1 is present for the 1,25(OH)2D3 synthesis. Interestingly, the liver mitochondrial fraction prepared from Cyp27b1 KO mice converted 25(OH)D3 to 1,25(OH)2D3. The most probable candidate is Cyp27a1. Our findings suggest that 25(OH)D3 may be useful for the treatment and prevention of osteoporosis for patients with chronic kidney disease.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Conservadores da Densidade Óssea/farmacologia , Calcifediol/farmacologia , Calcitriol/biossíntese , Calcitriol/sangue , Raquitismo/tratamento farmacológico , Animais , Densidade Óssea/efeitos dos fármacos , Calcitriol/genética , Cálcio/sangue , Colestanotriol 26-Mono-Oxigenase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoporose/tratamento farmacológico , Hormônio Paratireóideo/sangue , Fósforo/sangue , Vitamina D3 24-Hidroxilase/biossíntese , Vitamina D3 24-Hidroxilase/genética
13.
PLoS One ; 13(10): e0199856, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30281599

RESUMO

Calcium (Ca) absorption from the intestinal tract is promoted by active vitamin D (1α,25D3). Vitamin D not only promotes Ca homeostasis, but it also inhibits bone resorption and promotes osteogenesis, thus playing a role in the maintenance of normal bone metabolism. Because 1α,25D3 plays an important role in osteogenesis, vitamin D formulations, such as alfacalcidol (ALF) and eldecalcitol (ELD), are used for treating osteoporosis. While it is known that, in contrast to ALF, ELD is an active ligand that directly acts on bone, the reason for its superior osteogenesis effects is unknown. Cyp27b1-knockout mice (Cyp27b1-/-mice) are congenitally deficient in 1α,25D3 and exhibit marked hypocalcemia and high parathyroid hormone levels, resulting in osteodystrophy involving bone hypocalcification and growth plate cartilage hypertrophy. However, because the vitamin D receptor is expressed normally in Cyp27b1-/-mice, they respond normally to 1α,25D3. Accordingly, in Cyp27b1-/-mice, the pharmacological effects of exogenously administered active vitamin D derivatives can be analyzed without being affected by 1α,25D3. We used Cyp27b1-/-mice to characterize and clarify the superior osteogenic effects of ELD on the bone in comparison with ALF. The results indicated that compared to ALF, ELD strongly induces ECaC2, calbindin-D9k, and CYP24A1 in the duodenum, promoting Ca absorption and decreasing the plasma concentration of 1α,25D3, resulting in improved osteogenesis. Because bone morphological measurements demonstrated that ELD has stronger effects on bone calcification, trabecular formation, and cancellous bone density than ALF, ELD appears to be a more effective therapeutic agent for treating postmenopausal osteoporosis, in which cancellous bone density decreases markedly. By using Cyp27b1-/-mice, this study was the first to succeed in clarifying the osteogenic effect of ELD without any influence of endogenous 1α,25D3. Furthermore, ELD more strongly enhanced bone mineralization, trabecular proliferation, and cancellous bone density than did ALF. Thus, ELD is expected to show an effect on postmenopausal osteoporosis, in which cancellous bone mineral density decreases markedly. In the future, this study may enable the development of next-generation active vitamin D derivatives with higher affinity for bone than ELD.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Hidroxicolecalciferóis/farmacologia , Osteogênese/efeitos dos fármacos , Vitamina D/análogos & derivados , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Animais , Peso Corporal , Cálcio/metabolismo , Linhagem Celular Tumoral , Feminino , Fêmur/diagnóstico por imagem , Humanos , Masculino , Camundongos , Camundongos Knockout , Osteoporose Pós-Menopausa/tratamento farmacológico , Receptores de Calcitriol , Tíbia/diagnóstico por imagem , Transfecção , Vitamina D/metabolismo , Vitamina D/farmacologia
14.
Clin Epigenetics ; 10(1): 118, 2018 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-30208925

RESUMO

BACKGROUND: A variety of abnormalities in vitamin D metabolism have been reported in patients with active tuberculosis. However, intervention trials have produced inconsistent results. We hypothesized that genetic and epigenetic changes in the key genes of the vitamin D metabolic pathway may partly explain the differences between studies. METHODS: We performed a case-control study followed by a prospective cohort study. We recruited 122 patients with pulmonary tuberculosis and 118 healthy controls. The serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were measured. The methylation of the promoter regions of key genes in the vitamin D metabolic pathway (CYP24A1, CYP27A1, CYP27B1, CYP2R1, and VDR) was detected using the Illumina MiSeq platform. The specific methylation profiles were examined as epigenetic biomarkers. The sensitivity, specificity, and receiver operating characteristic (ROC) curves were used to estimate the predictive value of the biomarkers. RESULTS: The baseline serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations in the cases were significantly lower than those in the controls (51.60 ± 27.25 nmol/L vs. 117.50 ± 75.50 nmol/L, Z = - 8.515, P < 0.001; 82.63 ± 51.43 pmol/L vs. 94.02 ± 49.26 pmol/L, Z = - 2.165, P = 0.03). We sequenced 310 CpG sites in five candidate genes. After Bonferroni correction, there were 55 differentially methylated CpG sites between cases and controls; 41.5% were in the CYP27B1 gene, 31.7% were in the CYP24A1 gene, 14.7% were in the VDR gene, and 12.3% were in the CYP27A1 gene. When we designated the CpG sites that remained significant after the Bonferroni correction as the biomarkers, the area under the curve (AUC) for the cumulative methylation was 0.810 (95% CI 0.754-0.866). There was an interaction between CYP27A1 methylation level and 1,25-dihydroxyvitamin D concentration associated with the risk of TB (ORinteraction = 4.11, 95% CI 1.26-13.36, P = 0.019). The serum 1,25-dihydroxyvitamin D concentration at the end of the intensive treatment stage was related to a patient's prognosis (P = 0.008). There were 23 CpG sites that were individually related to the treatment outcomes, but the relationships were not significant after the Bonferroni correction. CONCLUSION: Both serum vitamin D concentrations and the methylation levels of key genes in the vitamin D metabolic pathway are related to the risk and prognosis of tuberculosis.


Assuntos
Metilação de DNA , Redes e Vias Metabólicas , Tuberculose/genética , Vitamina D/análogos & derivados , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Adulto , Idoso , Estudos de Casos e Controles , Colestanotriol 26-Mono-Oxigenase/genética , Epigênese Genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Regiões Promotoras Genéticas , Estudos Prospectivos , Curva ROC , Receptores de Calcitriol/genética , Análise de Sequência de DNA , Tuberculose/sangue , Vitamina D/sangue , Vitamina D3 24-Hidroxilase/genética
15.
Exp Dermatol ; 27(11): 1201-1209, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30066343

RESUMO

Renal 25-hydroxyvitamin D-1α-hydroxylase (1αOHase, CYP27B1) and 24-hydroxylase (24OHase, CYP24A1) are tightly regulated. However, little is known about the regulation of 1α(OH)ase and 24(OH)ase in extrarenal tissue such as the epidermis. This study was to determine the roles of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF 23) in the regulation of 1α(OH)ase and 24(OH)ase in epidermal keratinocytes as well as epidermal keratinocyte proliferation and differentiation. The results showed that PTH increased the protein level of 1α(OH)ase in human epidermal keratinocyte cell line HaCaT, but had no effect on the level of 24(OH)ase. The effect of PTH on 1α(OH)ase was blocked by the PKC inhibitor. Treatment with FGF23 decreased mRNA and protein levels of 1α(OH)ase and increased mRNA and protein levels of 24(OH)ase in HaCaT cells. The effect of FGF23 on 1α(OH)ase and 24(OH)ase was blocked by the mitogen-activated protein kinase/extracellular regulated protein kinase (MAPK/ERK) inhibitor. In addition, treatment with PTH enhanced levels of differentiation markers including keratin 1, involucrin, loricrin, and filaggrin but reduced levels of BrdU incorporation in HaCaT cells. These effects were inhibited by the PKC inhibitor. FGF23 enhanced proliferation of HaCaT cells, but reduced levels of early differentiation markers including keratin 1 and involucrin and enhanced levels of the later differentiation markers including loricrin and filaggrin. These results suggest that PTH stimulates 1α(OH)ase expression and differentiation of HaCaT cells and inhibits proliferation via PKC. The data also suggest that FGF23 inhibits 1α(OH)ase expression and stimulates 24(OH)ase expression via MAPK/ERK. In addition, FGF23 enhances proliferation and late differentiation and inhibits early differentiation of HaCaT keratinocytes.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Epiderme/enzimologia , Fatores de Crescimento de Fibroblastos/farmacologia , Queratinócitos/enzimologia , Hormônio Paratireóideo/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Vitamina D3 24-Hidroxilase/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Epiderme/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Glucuronidase/metabolismo , Humanos , Indóis/farmacologia , Queratinócitos/metabolismo , Maleimidas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Transdução de Sinais , Vitamina D3 24-Hidroxilase/genética
16.
Breast Cancer Res ; 20(1): 70, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29996894

RESUMO

BACKGROUND: Vitamin D has anticarcinogenic and immune-related properties and may protect against some diseases, including breast cancer. Vitamin D affects gene transcription and may influence DNA methylation. METHODS: We studied the relationships between serum vitamin D, DNA methylation, and breast cancer using a case-cohort sample (1070 cases, 1277 in subcohort) of non-Hispanic white women. For our primary analysis, we used robust linear regression to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and methylation within a random sample of the cohort ("subcohort"). We focused on 198 CpGs in or near seven vitamin D-related genes. For these 198 candidate CpG loci, we also examined how multiplicative interactions between methylation and 25(OH)D were associated with breast cancer risk. This was done using Cox proportional hazards models and the full case-cohort sample. We additionally conducted an exploratory epigenome-wide association study (EWAS) of the association between 25(OH)D and DNA methylation in the subcohort. RESULTS: Of the CpGs in vitamin D-related genes, cg21201924 (RXRA) had the lowest p value for association with 25(OH)D (p = 0.0004). Twenty-two other candidate CpGs were associated with 25(OH)D (p < 0.05; RXRA, NADSYN1/DHCR7, GC, or CYP27B1). We observed an interaction between 25(OH)D and methylation at cg21201924 in relation to breast cancer risk (ratio of hazard ratios = 1.22, 95% confidence interval 1.10-1.34; p = 7 × 10-5), indicating a larger methylation-breast cancer hazard ratio in those with high serum 25(OH)D concentrations. We also observed statistically significant (p < 0.05) interactions for six other RXRA CpGs and CpGs in CYP24A1, CYP27B1, NADSYN1/DHCR7, and VDR. In the EWAS of the subcohort, 25(OH)D was associated (q < 0.05) with methylation at cg24350360 (EPHX1; p = 3.4 × 10-8), cg06177555 (SPN; p = 9.8 × 10-8), and cg13243168 (SMARCD2; p = 2.9 × 10-7). CONCLUSIONS: 25(OH)D concentrations were associated with DNA methylation of CpGs in several vitamin D-related genes, with potential links to immune function-related genes. Methylation of CpGs in vitamin D-related genes may interact with 25(OH)D to affect the risk of breast cancer.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA/genética , Receptores de Calcitriol/genética , Vitamina D3 24-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Adulto , Idoso , Neoplasias da Mama/patologia , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Vitamina D/análogos & derivados , Vitamina D/genética , Vitamina D/metabolismo
17.
Am J Reprod Immunol ; 80(5): e13022, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30051540

RESUMO

Recurrent pregnancy loss (RPL) affects approximately 1%-2% of reproductive women. Auto- and cellular immune responses seem to be associated with RPL. Vitamin D (VD) has been shown to play a role in the modulation of the immune system. Effects of VD deficiency (VDD) in pregnancy have been associated with preeclampsia, gestational diabetes, fetal growth restriction, preterm labor, and sporadic spontaneous abortion (SA). We systematically reviewed articles that studied women with 2 or more SA and its association with VD. Eleven studies were included. Studies reported a high prevalence of VD insufficiency (VDI) or VDD in women with RPL and suggested that this could be associated with immunological dysregulation and consequently with RPL. Immunological benefits were reported in the peripheral blood of women with RPL after VD exposure. Thus, it is possible to speculate a beneficial role for VD supplementation in RPL. It seems that there are not differences in the vitamin D receptor (VDR) and CYP27B1 expression in endometrium of women with RPL but, in villous and decidual tissues, RPL women seem to have a decreased expression of VDR and, perhaps, a decreased expression of CYP27B1. Further randomized controlled studies are required to investigate the association between VDD or VDI and RPL.


Assuntos
Aborto Espontâneo/metabolismo , Decídua/metabolismo , Deficiência de Vitamina D/epidemiologia , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Aborto Espontâneo/epidemiologia , Autoimunidade , Feminino , Humanos , Imunidade Celular , Gravidez , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Recidiva
18.
J Steroid Biochem Mol Biol ; 183: 221-227, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30004013

RESUMO

Recently, we successfully generated a novel detection system for vitamin D receptor (VDR) ligands in vivo and in vitro, using a split-luciferase technique called the LucN-LBD-LucC biosensor that is a chimeric fusion protein of firefly luciferase with the ligand binding domain (LBD) of VDR. In this system, the luciferase light intensity of the LucN-LBD-LucC biosensor was decreased by binding of VDR ligands. Although this system is quite useful for evaluation of VDR ligands in a short time, the sensitivity of the LucN-LBD-LucC biosensor is not high enough. In this study, LXXLL motif peptides involved in the interaction between LBD and coactivators, such as the steroid receptor coactivator-1 (SRC-1), transcriptional intermediary factor 2 (TIF2), and the vitamin D receptor interacting protein 205 (DRIP205) were each inserted between LucN and LBD of the LucN-LBD-LucC biosensor. Surprisingly, the resulting LucN-LXXLL-LBD-LucC biosensor increased the light intensity in response to natural VDR ligands. This high-sensitivity biosensor system may be a powerful tool for discovery of high-affinity ligands for the mutant VDR. In addition, we have successfully estimated the activity of the wild-type and mutant CYP27B1 using the LucN-LXXLL-LBD-LucC biosensor in living cells within 90 min.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Técnicas Biossensoriais/métodos , Luciferases/metabolismo , Mutação , Receptores de Calcitriol/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Animais , Células COS , Humanos , Ligantes , Receptores de Calcitriol/genética
19.
Sci Rep ; 8(1): 9024, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899561

RESUMO

Recently, the antiproliferative action of 1,25(OH)2D3 (1,25D3), an active metabolite of vitamin D3, in the management of prostate cancer has been argued rigorously. In this study, we found that at a physiological concentration, 25(OH)D3 (25D3), the precursor of 1,25D3 and an inactive form of vitamin D because of its much weaker binding activity to the vitamin D receptor (VDR) compared with 1,25D3, had a gene expression profile similar to that of 1,25D3 in prostate cancer LNCaP cells. By immunocytochemistry, western blotting, and CYP27B1 and/or VDR knockdown by small interfering RNAs, we found that 10-7 M 25D3, which is within its uppermost physiological concentration in the bloodstream, induced VDR nuclear import and robustly activated its target genes in the virtual absence of CYP27B1 expression. Comprehensive microarray analyses verified 25D3 bioactivity, and we found that 25D3 target gene profiles largely matched those of 1,25D3, while the presence a small subset of 25D3- or 1,25D3-specific target genes was not excluded. These results indicated that 25D3 shares bioactivity with 1,25D3 without conversion to the latter. Metallothionein 2A was identified as a 1,25D3-specific repressive target gene, which might be a prerequisite for 1,25D3, but not 25D3, to exert its anti-proliferative action in LNCaP cells.


Assuntos
Calcifediol/farmacologia , Calcitriol/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Próstata/genética , Transcriptoma/efeitos dos fármacos , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Calcifediol/química , Calcitriol/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Humanos , Hidroxilação , Masculino , Metalotioneína , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitaminas/farmacologia
20.
Biomed Pharmacother ; 106: 54-60, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29957466

RESUMO

Chronic kidney disease-mineral and bone disorder (CKD-MBD) play a critical role in the pathogenesis of cardiovascular complications in patients with chronic kidney disease (CKD). Zuogui pill as a traditional Chinese herbal drug has been used for nourish kidney essence improve bone malnutrition of renal bone disease by regulating the metabolism of calcium and phosphorus and participating in osteoblast metabolism. In the present study, 5/6 nephrectomy rat model was used to reveal the mechanism of zuogui pill in treatment of CKD-MBD. Compared with sham rats, the levels of serum phosphorus, PTH, iPTH and creatinine were significantly decreased, while the serum calcium level was significantly increased, and the Cbfa1 protein level was significantly decreased and FGF23 protein level was significantly increased by Zuogui pill treatment. Compared with model rats, the BMD of rat was significantly increased by Zuogui pill treatment. Histological analysis revealed that the kidney injury of rats with CKD was significantly reduced by zuogui pill treatment. Compared with model rats, the CYP27B1 mRNA level was significantly increased, and the PTH mRNA level and NaPiIIa protein level were significantly decreased in the kidney by zuogui pill treatment. We inferred that zuogui pill exhibited potential therapeutic effects on CKD-MBD in the rats by regulating bone metabolism and nourish kidney.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Rim/efeitos dos fármacos , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Animais , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Cálcio/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Subunidade alfa 1 de Fator de Ligação ao Core/sangue , Creatinina/sangue , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/sangue , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/genética , Fósforo/sangue , Ratos Wistar , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/metabolismo
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