Association of vitamin D receptor gene polymorphisms with type 2 diabetes mellitus in Taif population: a case-control study / Associação de polimorfismos do gene do receptor de vitamina D com diabetes mellitus tipo 2 na população Taif: um estudo de caso-controle

Abstract Several reasons may underlie the dramatic increase in type2 diabetes mellitus. One of these reasons is the genetic basis and variations. Vitamin D receptor polymorphisms are associated with different diseases such as rheumatoid arthritis and diabetes. The aim of this study is to investigate the possible association of two identified mutations ApaI (rs7975232) and TaqI (rs731236). Eighty-nine healthy individuals and Fifty-six Type 2 Diabetic (T2D) patients were investigated using RFLP technique for genotyping and haplotyping as well. The distribution of Apal genotypes was not statistically significant among the control (P=0.65) as well as for diabetic patients (P=0.58). For Taql allele frequencies of T allele was 0.61 where of G allele was 0.39. The frequency distribution of Taql genotypes was not statistically significant among the control (P=0.26) as well as diabetic patients (P=0.17). Relative risk of the allele T of Apa1 gene is 1.28 and the odds ratio of the same allele is 1.53, while both estimates were < 1.0 of the allele G. Similarly, with the Taq1 gene the relative risk and the odds ratio values for the allele T are 1.09 and 1.27 respectively and both estimates of the allele C were 0.86 for the relative risk and 0.79 for the odds ratio. The pairwise linkage disequilibrium between the two SNPs Taq1/apa1 was statistically significant in control group (D = 0.218, D' = 0.925 and P value < 0.001) and similar data in diabetic groups (D = 0.2, D' = 0.875 and P value < 0.001). These data suggest that the T allele of both genes Apa1 and Taq1 is associated with the increased risk of type 2 diabetes. We think that we need a larger number of volunteers to reach a more accurate conclusion.

Resumo Várias razões podem estar subjacentes ao aumento dramático da diabetes mellitus tipo 2. Um desses motivos é a base genética e variações. Os polimorfismos do receptor da vitamina D estão associados a diferentes doenças, como artrite reumatoide e diabetes. O objetivo deste estudo é investigar a possível associação de duas mutações identificadas ApaI (rs7975232) e TaqI (rs731236). Oitenta e nove indivíduos saudáveis ​​e 56 pacientes com diabetes tipo 2 (T2D) foram investigados usando a técnica RFLP para genotipagem e haplotipagem também. A distribuição dos genótipos Apal não foi estatisticamente significativa entre o controle (P = 0,65), bem como para os pacientes diabéticos (P = 0,58). Para as frequências do alelo Taql, o alelo T foi de 0,61, onde o alelo G foi de 0,39. A distribuição de frequência dos genótipos Taql não foi estatisticamente significativa entre o controle (P = 0,26), bem como os pacientes diabéticos (P = 0,17). O risco relativo do alelo T do gene Apa1 é 1,28 e a razão de chances do mesmo alelo é 1,53, enquanto ambas as estimativas foram < 1,0 do alelo G. Da mesma forma, com o gene Taq1, os valores de risco relativo e razão de chances para o alelo T são 1,09 e 1,27, respectivamente, e ambas as estimativas do alelo C foram de 0,86 para o risco relativo e 0,79 para o odds ratio. O desequilíbrio de ligação par a par entre os dois SNPs Taq1 / apa1 foi estatisticamente significativo no grupo de controle (D = 0,218, D' = 0,925 e valor P < 0,001) e dados semelhantes em grupos diabéticos (D = 0,2, D' = 0,875 e valor P < 0,001). Esses dados sugerem que o alelo T de ambos os genes Apa1 e Taq1 está associado ao aumento do risco de diabetes tipo 2. Achamos que precisamos de um número maior de voluntários para chegar a uma conclusão mais precisa.

Exploring the expression profile of vitamin D receptor and its related long non-coding RNAs in patients with acute lymphoblastic leukemia

SUMMARY OBJECTIVE: Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. Previous studies have indicated the involvement of vitamin D receptor (VDR) and related long noncoding RNAs (lncRNAs) signaling in the pathophysiology of several cancers. However, their contribution to ALL remains to be elucidated. METHODS: In this case-control study, 30 patients with newly diagnosed ALL and 30 age- and sex-matched healthy children were selected. Then, the level of 25(OH) vitamin D and the expression of VDR and four VDR-related lncRNAs were assessed. RESULTS: No significant difference in serum 25(OH) vitamin D was observed between patients with ALL (20.42±6.5 ng/mL) and healthy subjects (25.45±11 ng/mL). In addition, the expression of MALAT-1, HOTAIR, and P-21 was not statistically significant between the two groups. However, a significant reduction in VDR and H19 expression was observed in patients with ALL (p<0.05). CONCLUSIONS: 25(OH) vitamin D insufficiency was evident in both groups. VDR and H19 signaling might be contributed to the pathogenesis of ALL, which needs further investigations.

Polymorphisms of the vitamin D receptor gene in Crohn's disease / Polimorfismos do gene do receptor de vitamina D na doença de Crohn

Introduction: Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions of the gastrointestinal tract. Studies have shown that polymorphisms of the vitamin D receptor (VDR) gene may help elucidate the pathogenesis of CD. Objectives: To analyze the role of VDR gene polymorphisms (ApaI, BsmI, FokI, and TaqI) in the development of CD. Methods: The present study is a systematic review with meta-analysis. a total of 50 articles in English and Portuguese published from 2000 to 2020 were selected from 3 databases. The relationship between CD and the VDR gene was addressed in 16 articles. Results: The TaqI polymorphism was analyzed in 3,689 patients and 4,645 control subjects (odds ratio [OR]=0.948; 95% confidence interval [95%CI]=0.851-1.056; p=0.3467). The ApaI polymorphism was studied in 3,406 patients and 4,415 control subjects (OR=1,033; 95%CI=0.854-1.250; p=0.7356). For FokI polymorphism, there were 2,998 patients and 4,146 control subjects (OR=0.965; 95%CI=0.734-1.267; p=0.7958). Lastly, the BsmI polymorphism was analyzed in 2,981 patients and 4,477 control subjects (OR=1,272; 95%CI=0.748-2.161; p=0.3743). Conclusion: These four VDR gene polymorphisms were not associated with CD. Therefore, further studies with larger samples are required to corroborate or rectify the conclusions from the present meta-analysis. (AU)

Introdução: A doença de Crohn (DC) e a retocolite ulcerativa (RU) são condições inflamatórias crônicas do trato gastrointestinal. Estudos indicam que os polimorfismos do gene do receptor de vitamina D (RVD) são promissores para a patogênese da DC. Objetivos: Avaliar papel dos os polimorfismos do gene do RVD (ApaI, BsmI, FokI e TaqI) no desenvolvimento da DC. Métodos: Trata-se de uma revisão sistemática com metanálise. Foram identificados 50 artigos em inglês e português publicados entre 2000 a 2020 em 3 bases de dados. Destes, foram selecionados 16 artigos que contemplavama relação entre a DC e o genedo RVD. Resultados: Para o polimorfismo TaqI, a amostra foi composta por 3.689 pacientes e 4.645 controles (razão de probabilidade [RP]=0,948; intervalo de confiança de 95% [IC95%]=0,851-1,056; p=0,3467). Para o polimorfismo ApaI, 3.406 pacientes e 4.415 controles (RP=1,033; IC95%=0,854-1,250; p=0,7356). Para o polimorfismo FokI, 2.998 pacientes e 4.146 controles (RP=0,965; IC95%=0,734-1,267; p=0,7958). E, para o polimorfismo BsmI, 2.981 pacientes e 4.477 controles (RP =1,272; IC95%=0,748-2,161; p=0,3743). Conclusão: Esses quatro polimorfismos do gene do RVD não apresentaram associação coma DC. Logo, sugere-se a realização de mais estudos com amostras maiores a fimde corroborar ou retificar a conclusão desta metanálise. (AU)

Effect of vitamin D3 supplementation on 25 OHD plasma levels in the presence of VDR gene polymorphisms / Efecto de la suplementación con vitamina D3 en los niveles plasmáticos de 25 OHD, en presencia de polimorfismos del gen VDR

The objective of this review was to investigate the effect of vitamin D3 supplementation on serum 25-hydroxyvitamin D concentration in individuals with single-nucleotide polymorphisms in the vitamin D receptor gene. The research was conducted on 241 articles found in the PubMed, Scopus, Science Direct, and Cochrane Library databases between November and December 2018. After article screening, three randomized double-blind placebo-controlled clinical trials were identified as eligible for this review. Participants were Australian, Brazilian, and Chinese individuals, who ingested doses of vitamin D3 ranging from 2000 IU to a megadose of 200,000 IU. The presence of the BB/Bb genotype of the BsmI polymorphism and the FokI G allele caused an increase in the serum concentrations of vitamin D after supplementation. Nonetheless, the few studies on this subject are not unanimous in their results. It is possible that differences among populations, sample sizes, doses, and time of supplementation have an impact on data and outcomes.

El objetivo de esta revisión fue investigar el efecto de la suplementación con vitamina D3 sobre la concentración sérica de 25-hidroxivitamina D en individuos con los polimorfismos de un solo nucleótido en el gen del receptor de la vitamina D. La investigación se realizó en 241 artículos encontrados en las bases de datos PubMed, Scopus, Science Direct y Cochrane Library entre noviembre y diciembre de 2018. Después de la selección del artículo, se identificaron tres ensayos clínicos aleatorios, controlados con placebo, doble ciego, como elegibles para esta revisión. Los participantes fueron australianos, brasileños y chinos, quienes ingirieron dosis de vitamina D3 que iban desde las 2000 UI hasta una megadosis de 200,000 UI. La presencia del genotipo BB / Bb del polimorfismo BsmI y el alelo FokI G causó un aumento en las concentraciones séricas de vitamina D después de la suplementación. No obstante, los pocos estudios sobre este tema no son unánimes en sus resultados. Es posible que las diferencias entre poblaciones, tamaños de muestra, dosis y tiempo de suplementación tengan un impacto en los datos y resultados de la investigación.

Association between estrogen, vitamin d and microrna17 gene polymorphisms and periapical lesions

Abstract This study evaluated the association between polymorphisms in genes encoding estrogen receptors 1 (ESR1) and 2 (ESR2), vitamin D receptor (VDR) and in microRNA17 (which binds to ESR1 and VDR) with persistent apical periodontitis (PAP) after the endodontic treatment. We included 162 patients who completed endodontic treatment at least one year ago and presented apical periodontitis at the beginning of the root canal therapy. Clinical and radiographic exams were performed to evaluate the presence of PAP or healthy periradicular tissues (healed). Saliva samples were collected as a genomic DNA. The genotyping of ESR1 (rs2234693 and rs9340799), ESR2 (rs1256049 and rs4986938), VDR (rs739837 and rs2228570) and miRNA17 (rs4284505) were performed by real-time PCR. Chi-square test was used to the distribution of genotype and allele frequencies. Haplotype analysis was also performed. Eighty-nine patients were included in the "healed" group and 73 in the "PAP" group. No association was found between the allelic and genotypic polymorphisms studied and PAP (p>0.05). Haplotype analysis also did not demonstrated an association (p>0.05). In conclusion, the genetic polymorphisms in ESR1, ESR2, VDR and miRNA17 are not associated with PAP.

Resumo Este estudo avaliou a associação entre polimorfismos em genes que codificam os receptores de estrogênio 1 (ESR1) e 2 (ESR2), receptor de vitamina D (VDR) e no microRNA17 (que se liga à ESR1 e VDR) e a periodontite apical persistente (PAP) após o tratamento endodôntico. Foram incluídos 162 pacientes com tratamento endodôntico concluído há pelo menos um ano e que apresentavam periodontite apical no início da terapia endodôntica. Exames clínicos e radiográficos foram realizados para avaliar a presença de PAP ou tecidos perirradiculares saudáveis (cicatrizados). As amostras de saliva foram coletadas como fonte de DNA genômico. A genotipagem de ESR1 (rs2234693 e rs9340799), ESR2 (rs1256049 e rs4986938), VDR (rs739837 e rs2228570) e miRNA17 (rs4284505) foram realizadas por PCR em tempo real. O teste do qui-quadrado foi utilizado para a distribuição das frequências genotípicas e alélicas. A análise de haplótipos também foi realizada. Oitenta e nove pacientes foram incluídos no grupo "curado" e 73 no grupo "PAP". Não foi encontrada associação entre os polimorfismos alélicos e genotípicos estudados e a PAP (p>0,05). Concluí-se que os polimorfismos genéticos em ESR1, ESR2, VDR e miRNA17 não estão associados à PAP.

Chronic Periodontitis in Patients with Type 2 Diabetes: Analysis of the FokI Polymorphism and Perception of Quality of Life

Abstract Objective: To analyze whether the FokI polymorphism (rs228570) present in the vitamin D receptor gene in type 2 diabetics is related to chronic periodontitis's clinical status and evaluates the influence of chronic periodontitis on the perception of quality of life. Material and Methods: It is a clinical and laboratory study, composed of a sample of 59 individuals with previous diagnosis of type 2 Diabetes Mellitus and chronic periodontitis, of both sexes. On clinical examination, socio-epidemiological data and quality of life of patients with the Oral Health Impact Profile (OHIP-14) were recorded and a periogram was performed. Subsequently, saliva was collected spontaneously in sterile Falcon tubes (15 ml) and stored in the freezer at -20 °C. The purification of the genetic material was done with a PROMEGA kit (Wizard®), and the polymorphism studied was FokI (rs228570), found in the vitamin D receptor promoting region, with rs: 228570. After extraction of saliva DNA and purification, genotyping was performed by real-time PCR using specific allele probes (TaqMan® System). Results: The polymorphism of the vitamin D receptor gene was not positively associated with the severity and clinical characteristics of periodontitis, but suggested a relationship with the extent of the disease. Periodontitis also had no positive association with patients' perception of quality of life. Conclusion: The perception of quality of life of patients with chronic periodontitis and type 2 diabetes mellitus was compromised by the systemic condition, secondary to oral health, although some dimensions of OHIP-14 have been more frequently mentioned, such as psychological discomfort, physical pain and physical disability.

Influence of Polymorphism of Vitamin D Receptor (Fok I) on Hypertension

Abstract Evidence suggests that polymorphisms in the gene encoding a vitamin D receptor might affect blood pressure. The objective of this systematic review was to investigate the association between hypertension and vitamin D receptor (Fok I) gene polymorphism. A literature search was performed according to the PRISMA guidelines using the MEDLINE®/PubMed, Scopus, Cochrane Library CENTRAL, SciELO, and LILACS databases. The quality of case-control or cohort studies and studies based on cross-sectional methodology was evaluated using the Newcastle-Ottawa Scale and the protocol of Loney and coauthors [25], respectively. In this systematic literature search, 215 publications were identified, of which 10 were analyzed, including seven case-control studies, two cross-sectional studies, and one cohort study. The association between Fok I polymorphism and hypertension was reported in 60% of the publications and the risk for hypertension was shown to be related to FF and ff genotypes. In addition, Fok I polymorphism was shown to increase plasma renin activity, which plays an important role in regulating blood pressure. However, no association was observed between Fok I polymorphism and serum vitamin D levels. In conclusion, Fok I polymorphism plays an important role in hypertension.

Vitamin D, vitamin D binding protein, vitamin D receptor levels and cardiac dysautonomia in patients with multiple sclerosis: a cross-sectional study / Vitamina D, proteína de ligação à vitamina D, níveis de receptores de vitamina D e disautonomia cardíaca em pacientes com esclerose múltipla: um estudo transversal

ABSTRACT Vitamin D is a pleiotropic steroid hormone that modulates the autonomic balance. Its deficiency has been described as an environmental risk factor for multiple sclerosis (MS). The aim of this study was to investigate the serum levels of vitamin D, vitamin D binding protein (VDBP) and vitamin D receptors (VDR) and to evaluate cardiac dysautonomia in MS patients due to bidirectional interaction between vitamin D and the autonomic nervous system. Methods: The current cross-sectional study was conducted on 26 patients with relapsing-remitting MS and on 24 healthy controls. Twenty-four-hour ambulatory blood pressure variability (BPV) was calculated and the participants were evaluated for orthostatic hypotension and supine hypertension. Serum levels of vitamin D, VDBP and VDR were measured. Results: The mean serum vitamin D level was significantly lower in MS patients than in controls (p = 0.044); however there was no significant difference in terms of VDR and VDBP levels between the groups. Supine hypertension and orthostatic hypotension were significant and the 24-hour systolic BPV was significantly decreased in patients with MS (p < 0.05) compared to controls. No correlation was found between vitamin D, VDBP and VDR with supine hypertension, orthostatic hypotension and systolic BPV values (p > 0.05). Also, there was a negative correlation between VDBP and the EDSS (p = 0.039, r = −0.406). Conclusion: There was no correlation between orthostatic hypotension, supine hypertension and systolic BPV values and serum vitamin D, VDBP and VDR in MS patients. Future prospective studies with large number of patients may help us to better understand the relationship between vitamin D and the autonomic nervous system.

RESUMO A vitamina D é um hormônio esteroide pleiotrópico que modula o equilíbrio autonômico. Sua deficiência tem sido descrita como fator de risco ambiental para esclerose múltipla (EM). O objetivo deste estudo foi investigar os níveis séricos de vitamina D, proteína de ligação à vitamina D (VDBP) e receptor de vitamina D (VDR) e avaliar a disautonomia cardíaca em pacientes com EM devida à interação bidirecional entre vitamina D e sistema nervoso autônomo. Métodos: O presente estudo transversal foi realizado em 26 pacientes com EM remitente-recorrente e em 24 controles saudáveis. A variabilidade da pressão arterial ambulatorial (BPV) por 24 horas foi calculada e os participantes foram avaliados quanto à hipotensão ortostática e hipertensão supina. Os níveis séricos de vitamina D, VDBP e VDR foram medidos. Resultados: O nível sérico médio de vitamina D foi significativamente menor nos pacientes com EM do que nos controles (p = 0,044); no entanto, não houve diferença significativa em termos de níveis de VDR e VDBP entre os grupos. Hipertensão supina e hipotensão ortostática foram significativas e a BPV sistólica de 24 horas diminuiu significativamente em pacientes com EM (p < 0,05) em comparação aos controles. Não foi encontrada correlação entre vitamina D, VDBP e VDR com hipertensão supina, hipotensão ortostática e BPV sistólica (p > 0,05). Também houve correlação negativa entre VDBP e EDSS (p = 0,039, r = −0,406). Conclusão: Não houve correlação entre hipotensão ortostática, hipertensão supina e valores de BPV sistólica e vitamina D sérica, VDBP e VDR em pacientes com EM. Futuros estudos prospectivos com grande número de pacientes podem nos ajudar a entender melhor a relação entre vitamina D e sistema nervoso autônomo.

Assessment of polymorphismof the vdr gene and serum vitamin d values in gestational diabetes mellitus / Avaliação do polimorfismo do gene VDR e valores séricos de vitamina D no diabetes mellitus gestacional

Abstract Objective To evaluate the relationship between vitamin D receptor (VDR) gene polymorphism (FokI [rs10735810]) and serum vitamin D concentration in gestational diabetes mellitus (GDM). Methods A prospective case-control study that recruited healthy pregnant women (control group) (n = 78) and women with GDM (GDM group) (n = 79), with no other comorbidities. Peripheral blood samples were collected in the 3rd trimester of gestation, and all of the pregnant women were followed-up until the end of the pregnancy and the postpartum period. Serum vitamin D concentrations were measured by high-performance liquid chromatography (HPLC). For genomic polymorphism analysis, the genomic DNA was extracted by the dodecyltrimethylammonium bromide/ cetyltrimethylammonium bromide (DTAB/CTAB) method, and genotyping was performed by the polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) technique, using the restriction enzyme FokI. The Student-t, Mann- Whitney, chi-squared, and Fischer exact tests were used for the analysis of the results. Results There was no significant difference between the pregnant women in the control and GDM groups regarding serumvitamin D levels (17.60 ± 8.89 ng/mL versus 23.60 ± 10.68 ng/mL; p = 0.1). Also, no significant difference was detected between the FokI genotypic frequency when the 2 groups were compared with each other (p = 0.41). Conclusion There was no association between the FokI polymorphism and the development of GDM, nor was there any change in serum vitamin D levels in patients with GDM.

Resumo Objetivo Avaliar a relação entre o polimorfismo do gene receptor da vitamina D (VDR) (FokI [rs10735810]) e a concentração sérica de vitamina D no diabetes mellitus gestacional (DMG). Métodos Estudo prospectivo tipo caso-controle que recrutou gestantes saudáveis (grupo controle) (n = 78) e com DMG (grupo DMG) (n = 79), sem outras comorbidades. Foram coletadas amostras de sangue periférico no 3° trimestre da gestação, e todas as gestantes foram acompanhadas até o final da gravidez e no pós-parto. As concentrações séricas de vitamina D foram mensuradas por cromotografia líquida de alta eficiência (CLAE). Para análise do polimorfismo genético, o DNA genômico foi extraído pelo método de brometo de dodeciltrimetilamônio/brometo de cetiltrimetilamônio (DTAB/CTAB), e as genotipagens foram realizadas por técnica de reação de cadeia de polimerase - polimorfismo do comprimento do fragmento de restrição (PCRRFLP, na sigla em inglês), sendo empregada a enzima de restrição FokI. Foram utilizados os testes t-Student, Mann-Whitney, qui-quadrado e exato de Fischer para a análise dos resultados. Resultados Não houve diferença significativa entre as gestantes dos grupos controle e DMG quanto aos níveis séricos de vitamina D (17,60 ± 8,89 ng/mL versus 23,60 ± 10,68 ng/mL; p = 0,1). Também não foi detectada diferença significativa entre a frequência genotípica de FokI, quando comparados os 2 grupos entre si (p = 0,41). Conclusão Não foi identificada associação do polimorfismo FokI com o desenvolvimento de DMG, bem como não foi observada alteração nos níveis séricos de vitamina D em pacientes com DMG.

Association of vitamin D3, VDR gene polymorphisms, and LL-37 with a clinical form of Chagas Disease

Abstract INTRODUCTION: Chagas disease (CD) is an important public health problem in Brazil and worldwide. Aging and obesity are important matters in patients with CD, as is hypovitaminosis D3, which can decrease the quality of life of these patients. Immunomodulation mediated by vitamin D3, especially the production of antimicrobial peptides such as cathelicidin LL-37, might be related to the severity and symptoms of CD. This study aimed to determine the serum levels of vitamin D and LL-37 and VDR gene polymorphisms in patients with chronic CD. METHODS: This study included male patients with cardiac and indeterminate clinical forms of CD. Clinical, anthropometric, and blood parameters were obtained. Serum levels of 25(OH)D3 and LL-37 were determined by chemiluminescence and enzyme-linked immunosorbent assay respectively. Fok (rs731236), Bsm (rs1544410), Apa (rs7975232), and Taq (rs731236) polymorphisms of the VDR gene were investigated by PCR-RFLP. RESULTS: Sixty-four patients were included in the study: 18 of the cardiac form and 46 of the indeterminate form. No differences in age, ethnicity, BMI, arterial hypertension, diabetes mellitus, or dyslipidemias were observed between groups. However, the serum levels of 25(OH)D3, but not of LL-37, were lower in the cardiac form group. The association among polymorphisms, vitamin D, and clinical form was not significant. CONCLUSIONS: Decreased levels of vitamin D suggest an association with the cardiac form of CD. Studies investigating the roles of vitamin D and LL-37 in the immune response and their associations with VDR polymorphisms and disease susceptibility are necessary.

Stanozolol promotes osteogenic gene expression and apposition of bone mineral in vitro

Abstract Stanozolol (ST) is a synthetic androgen with high anabolic potential. Although it is known that androgens play a positive role in bone metabolism, ST action on bone cells has not been sufficiently tested to support its clinical use for bone augmentation procedures. Objective: This study aimed to assess the effects of ST on osteogenic activity and gene expression in SaOS-2 cells. Material and Methods: SaOS-2 deposition of mineralizing matrix in response to increasing doses of ST (0-1000 nM) was evaluated through Alizarin Red S and Calcein Green staining techniques at 6, 12 and 24 days. Gene expression of runt-related transcription factor 2 (RUNX2), vitamin D receptor (VDR), osteopontin (SPP1) and osteonectin (ON) was analyzed by RT-PCR. Results: ST significantly influenced SaOS-2 osteogenic activity: stainings showed the presence of rounded calcified nodules, which increased both in number and in size over time and depending on ST dose. RT-PCR highlighted ST modulation of genes related to osteogenic differentiation. Conclusions: This study provided encouraging results, showing ST promoted the osteogenic commitment of SaOS-2 cells. Further studies are required to validate these data in primary osteoblasts and to investigate ST molecular pathway of action.

BsmI polymorphism in the vitamin D receptor gene is associated with 25-hydroxy vitamin D levels in individuals with cognitive decline / Polimorfismo BsmI no gene do receptor de vitamina D está associado aos níveis de 25-hidroxi vitamina D em indivíduos com declínio cognitivo

ABSTRACT Elderly people are at a high risk of developing vitamin D (VitD) deficiency due to both decreased intake and cutaneous synthesis. Most of the biological actions of VitD are mediated by the vitamin D receptor (VDR), which is present in neurons and glial cells of the hippocampus, and in the cortex and subcortical nuclei, essential areas for cognition. It is known that VDR gene polymorphisms may decrease the VDR affinity for VitD. Objective: The present study aimed to investigate the influence of VitD levels on cognitive decline in patients with dementia due to Alzheimer's disease (AD, n = 32) and mild cognitive impairment (MCI, n = 15) compared to cognitively healthy elderly (n = 24). We also evaluated the association of VDR gene polymorphisms with cognitive disturbance. Methods: Four polymorphisms on the VDR gene were studied, namely, BsmI, ApaI, FokI and TaqI, by polymerase chain reaction-restriction fragment length polymorphism. Serum levels of 25-hydroxy vitamin D (25(OH)D) were determined by high performance liquid chromatography. Results: No significant difference in 25(OH)D levels or genotypic/allelic frequencies was observed between the groups. Deficiency of 25(OH)D was more frequently observed in women. The AA/AG genotypes of the BsmI polymorphism was associated with sufficient 25(OH)D levels, while the GG genotype of this same polymorphism was associated to insufficient levels in the cognitively-impaired group (individuals with AD or MCI). Conclusions: The data obtained do not confirm the relationship between reductions of VitD levels, polymorphisms in the VDR gene, and altered cognitive function in this sample. However, the data indicate that BsmI polymorphism in the VDR gene is associated with the VitD levels in individuals with cognitive decline.

RESUMO Idosos apresentam risco elevado de desenvolverem deficiência de Vitamina D (VitD) devido à diminuição da ingestão e da síntese na pele. A maioria das ações biológicas da VitD é mediada pelo receptor da vitamina D (VDR), que está presente nos neurônios e células gliais do hipocampo, e no córtex e em núcleos subcorticais, áreas essenciais para a cognição. Sabe-se que polimorfismos do gene VDR podem diminuir a afinidade do VDR pela VitD. Objetivo: O presente estudo teve como objetivo investigar a influência dos níveis de VitD no declínio cognitivo em pacientes com demência devida à doença de Alzheimer (DA, n = 32) e comprometimento cognitivo leve (CCL, n = 15) em comparação a um grupo de idosos cognitivamente saudáveis (n = 24). Nós também avaliamos a associação entre polimorfimos no gene do receptor de VitD e as alterações cognitivas. Métodos: Quatro polimorfismos no gene VDR foram estudados, sendo BsmI, ApaI, FokI e TaqI, por PCR-RFLP. Os níveis séricos de 25-hidroxi vitamina D (25(OH)D) foram determinados por HPLC. Resultados: Não houve diferença significativa nos níveis de 25(OH)D ou nas frequências genotípicas / alélicas entre os grupos. Níveis deficientes de 25(OH)D foram mais frequentes nas mulheres. Os genótipos AA / AG do polimorfismo BsmI foram associados a níveis suficientes de 25(OH)D, enquanto o genótipo GG deste mesmo polimorfismo foi associado a níveis insuficientes no grupo com comprometimento cognitivo (em indivíduos com DA ou CCL). Conclusões: Os resultados obtidos não confirmam a relação entre redução dos níveis de VitD, polimorfismos no gene VDR e função cognitiva alterada nesta amostra. No entanto, os dados indicam que o polimorfismo BsmI no gene VDR está associado aos níveis de VitD em indivíduos com declínio cognitivo.

Mutações do gene do receptor de vitamina d e níveis séricos de vitamina d em crianças com asma / Vitamin d receptor gene mutations and vitamin d serum levels in asthmatic children

RESUMO Objetivo: Verificar a relação dos polimorfismos do gene do receptor de vitamina D (RVD) com sinais clínicos e níveis de vitamina D (VD) em asmáticos. Métodos: Estudo transversal com 77 crianças de 7 a 14 anos de um ambulatório especializado, divididas em 3 grupos: asmáticos, em uso de corticoide inalatório (ICS) por mais de um ano; asmáticos sem necessidade de ICS; não asmáticos e não alérgicos (de acordo com o International Study of Asthma and Allergies in Childhood - ISAAC. Foram avaliados: espirometria, testes alérgicos, presença do polimorfismo CDX2 do promotor do RVD por reação em cadeia da polimerase (PCR) e genotipagem de polimorfismos dos éxons 2 e 3 por PCR-SSCA (single-strand conformational analysis), imunoglobulina E (IgE) total e IgE específica para ácaros e gramíneas nos três grupos estudados. Níveis de 25-hidroxivitamina D foram dosados nos asmáticos. Resultados: A média de idade foi 10,8±2,2 anos, 57% masculinos, 38 asmáticos com ICS, 22 sem ICS e 17 não asmáticos. Rinite alérgica esteve presente em 90% dos asmáticos, polimorfismo CDX2 em 23% dos asmáticos e ausente nos controles (p=0,03). Menores níveis de volume expiratório forçado no primeiro segundo (VEF1%) foram observados nos asmáticos homozigotos para CDX2 (p=0,001). Variações nas sequências dos éxons 2 e 3 não foram relacionadas com a asma ou demais testes. Deficiência ou insuficiência de VD foi diagnosticada em 98% dos asmáticos. Não houve associação entre níveis de VD e polimorfismos genéticos dos éxons 2 e 3. Conclusões: Observou-se associação positiva entre polimorfismo CDX2 em homozigoze com asma e menores valores de VEF1%. O CDX2 pode modificar a interação celular do RVD com a vitamina, bem como pode estar associado com a asma e com a dificuldade de controle da doença.

ABSTRACT Objective: To verify the relationship between polymorphisms of the vitamin D receptor gene (VDR), clinical findings, and serum vitamin D (VD) levels in asthmatics. Methods: A cross sectional study of 77 children aged 7 to 14 years old, who were attended at a specialized clinic. The children were divided into 3 groups: asthmatics who had been using inhaled corticosteroids (ICS) for more than one year; asthmatics who had not been using ICS; non-asthmatics, and children without allergies (according to the International Study of Asthma and Allergies in Childhood ­- ISAAC). Spirometry, skin prick tests, the presence of a VDR promoter CDX2 polymorphism from an allele-specific polimerase chain reaction (PCR), exons 2 and 3 polymorphisms genotyping by PCR-SSCA (single-strand conformational analysis), total immunoglobulin E (IgE) and specific IgE to mites and grass were evaluated in these three groups. Levels of 25-hydroxyvitamin D were determined in asthmatics only. Results: The mean age of the children was 10.8±2.0 years old, 57% were male, 38 were asthmatic and using ICS, 22 were asthmatic and not using ICS, and 17 were non-asthmatic. Allergic rhinitis was present in 90% of asthmatics. Homozygous CDX2 was detected in 23% of the patients and absent in the control group (p=0.03). Lower forced expiratory volume in 1 second (FEV1%) values were observed in CDX2 homozygous asthmatics (p=0.001). Variations in the exon 2 and 3 sequences were not related to asthma or the other tests. VD deficiency or insufficiency was detected in 98% of asthmatics. There was no association between VD levels and genetic polymorphisms from exons 2 and 3. Conclusions: There was a positive association between homozygous CDX2 polymorphism, asthma and lower FEV1% values. CDX2 is capable of modifying cell interaction between VDR and VD, and it could be associated with the prevalence of asthma, and the difficulty in controlling the disease.

Efeitos contrastantes da vitamina D sobre a resposta imune inata e adquirida e seu impacto na recuperação da tuberculose / Contrasting effects of Vitamin D on innate and acquired immune responses and its impact on tuberculosis recover

A vitamina D é um hormônio essencial para o organismo, podendo ser obtida da dieta ou, principalmente, gerada pela pele após exposição à luz solar ultravioleta B. Na sua forma ativa (1,25(oH)2D) ela controla a absorção de cálcio e fósforo do intestino para a corrente sanguínea e participa de diversos processos celulares e fisiológicos. A ligação da 1,25(oH)2D ao receptor da vitamina D (VDr) presente em diversas células, como as células do sistema imunológico, induz a transcrição de genes que podem, por exemplo, modular a resposta imune inata e adquirida. A deficiência de vitamina D ou do VDR é associada a problemas de saúde como desordens esqueléticas, hipertensão, doenças cardiovasculares, diabetes mellitus, dislipidemias, doenças autoimunes e doenças infecciosas. Neste sentido, a suplementação com vitamina D tem sido proposta como uma possível medida preventiva, podendo ser aplicada em muitas patologias, em especial na tuberculose. Principal causa de morte por um único agente infeccioso, a tuberculose é responsável por cerca de 1,3 milhões de óbitos por ano no mundo. Publicações recentes apontam efeitos diversos da vitamina D na resposta imune inata e adquirida. A 1,25(oH)2D3 na presença do interferon (IFN)-γ é capaz de aumentar a atividade bactericida do macrófago contra o M. tuberculosis, aumentando a produção de peptídios antimicrobianos e estimulando a autofagia, favorecendo assim a lise de bacilos localizados em fagossomos. Por outro lado, a vitamina D em linfócitos T mostra efeito tolerogênico que favorece o controle de respostas inflamatórias excessivas. Neste trabalho de revisão são apresentados estudos recentes envolvendo efeitos da vitamina D na resposta imune inata e adquirida. Além disso, considerações sobre deficiência de vitamina D e maior risco de contrair tuberculose, e efeitos contrastantes da suplementação com vitamina D na prevenção e tratamento da TB, são discutidos.

Vitamin D is an essential hormone for the body, and can be obtained from diet or, mainly, generated by the skin after exposure to ultraviolet B sunlight. In its active form (1.25(oH)2D) it controls the absorption of calcium and phosphorus from the intestine into the bloodstream and participates in several cellular and physiological processes. Binding of 1,25(oH)2D to the Vitamin D receptor (VDr) present in several cells, such as cells of the immune system, induces transcription of genes that can, for example, modulate the innate and adaptive immune response. Deficiency of Vitamin D or VDr is associated with health problems such as skeletal disorders, hypertension, cardiovascular disease, diabetes mellitus, dyslipidemias, autoimmune diseases and infectious diseases. In this sense, Vitamin D supplementation has been proposed as a possible preventive measure and can be applied in several pathologies, especially in tuberculosis. main cause of death by a single infectious agent, tuberculosis accounts for about 1.3 million deaths per year worldwide. recent publications point to contrasting functions of Vitamin D in the innate and acquired immune response. 1.25(oH)2D3 in the presence of interferon (IFN)-γ is capable of increasing the bactericidal activity of the macrophage against M. tuberculosis, increasing the production of antimicrobial peptides and stimulating autophagy, thus favoring the lysis of bacilli located in phagosomes. on the other hand, Vitamin D in T lymphocytes shows a tolerogenic effect that favors the control of excessive inflammatory responses. In this review, recent studies involving Vitamin D effects on the innate and acquired immune responses are presented. In addition, considerations about Vitamin D deficiency and increased risk of contracting tuberculosis, and contrasting effects of Vitamin D supplementation on the prevention and treatment of TB, are discussed.

Asociación de variantes polimorfas de los genes PTPN22 , TNF y VDR en niños con nefritis lúpica: un estudio de tríos en familias colombianas / Association of polymorphic variants of PTPN22 , TNF and VDR genes in children with lupus nephritis: A study in Colombian family triads

RESUMEN Introducción. El lupus eritematoso sistémico es una enfermedad autoinmunitaria cuya gravedad varía según la raza, el sexo y la edad de aparición. Esta disparidad también se observa en los marcadores genéticos asociados con la enfermedad presentes en los genes PTPN22, VDR y TNF. La estratificación genética que presentan las diferentes poblaciones en el mundo puede influir en dicha variabilidad. Objetivo. Analizar la asociación de variantes genéticas de los genes PTPN22, VDR y TNF con nefritis lúpica en niños y su caracter de hereditarias en familias colombianas. Materiales y métodos. Se llevó a cabo un estudio basado en familias con 46 tríos (caso, padre y madre). Se hizo la genotipificación de las variantes rs2476601 de PTPN22, rs361525 y rs1800629 del TNF, y TaqI [rs731236], ApaI [rs7975232], BsmI [rs1544410] y FokI [rs2228570] del VDR, mediante reacción en cadena de la polimerasa cuantitativa (quantitative Polymerase Chain Reaction, qPCR). Se estimó el efecto de la transmisión del alelo de riesgo de padres a hijos y el desequilibrio de ligamiento de los loci VDR y TNF. Resultados. Se observó que el alelo A de rs2476601 en PTPN22 se distribuyó en 8,69 % (n=16) de los padres y en 19,5 % (n=18) de los casos, y que su transmisión de padres a hijos fue 17 veces mayor con relación al alelo G (p=0,028). Los polimorfismos de TNF y VDR no presentaron desequilibrio de transmisión. Las variantes TaqI, ApaI y BsmI del VDR presentaron desequilibrio de ligamiento. Conclusión. Estos hallazgos evidenciaron una asociación del polimorfismo rs2476601 de PTPN22 con la nefritis lúpica en niños, determinada por su transmisión en el grupo de familias estudiadas.

ABSTRACT Introduction: Systemic lupus erythematosus is an autoimmune disease in which the severity varies according to race, sex and age of onset. This variation is also observed in the genetic markers associated with the disease, including PTPN22, VDR and TNF genes. The genetic stratification in different populations worldwide can influence the variability. Objective: To analyze the heritability of PTPN22, VDR and TNF genetic variants and their association with pediatric lupus nephritis in Colombian families. Materials and methods: We conducted a family-based study including 46 triads (case, father and mother). The variants rs2476601 of PTPN22; rs361525 and rs1800629 of TNF, and TaqI [rs731236], ApaI [rs7975232], BsmI [rs1544410] and FokI [rs2228570] of VDR were genotyped by qPCR. The effects of overtransmission of the risk allele from parents to children and linkage disequilibrium at the VDR and TNF loci were estimated. Results: We found that allele A of rs2476601 in PTPN22 was distributed among 8.69 % (n=16) of the parents and 19.5 % (n=18) of the cases; this allele was overtransmitted from parents to children 17 times more often than the G allele (p=0.028). TNF and VDR polymorphisms did not exhibit transmission disequilibrium. VDR TaqI, ApaI and BsmI variants exhibited linkage disequilibrium. Conclusion: These findings showed an association between the PTPN22 rs2476601 polymorphism and pediatric lupus nephritis due to its overtransmission in the group of families studied.

Women with recurrent spontaneous abortion have decreased 25(OH) vitamin D and VDR at the fetal-maternal interface

Immunological mechanisms have been proposed to underlie the pathogenesis of recurrent spontaneous abortion (RSA). Vitamin D has a potent immunomodulatory effect, which may affect pregnancy outcome. The objective of this study was to investigate 25-hydroxyvitamin D [25(OH) D] concentration and vitamin D receptor (VDR) expression in the decidual tissues of RSA patients. Thirty women with RSA (RSA group) and thirty women undergoing elective abortion (control group) were recruited during 2016 from gynecology outpatient clinics. We measured 25(OH) D, interleukin (IL)-17, IL-23, transforming growth factor β (TGF-β), VDR and 1-α-hydroxylase (CYP27B1) in decidual tissues collected during the abortion procedure. In the RSA group, 25(OH) D and TGF-β were significantly decreased while IL-17 and IL-23 were significantly increased compared with the control group. VDR expression was significantly decreased in the RSA group compared with the control group. Logistic regression analysis showed a significant negative correlation between 25(OH) D in decidual tissues and RSA. These results indicated that vitamin D concentrations in the decidua are associated with inflammatory cytokine production, suggesting that vitamin D and VDR may play a role in the etiology of RSA.

Metabolismo de la Vitamina D: rol en la génesis de enfermedades / Vitamin D metabolism: role in the genesis of diseases

La vitamina D clásicamente ha sido relacionada con el metabolismo óseo, sin embargo ejerce diversas funciones en varios tejidos del organismo que poseen el receptor para vitamina D (VCR) yson susceptibles a su efecto. La disminución de vitamina D también se ha asociado a patologías "no clásicas"como hipertensión, síndrome metabólico, resistencia a insulina, diabetes, desarrollo de algunos canceres,alteraciones pulmonares, autoinmunidad e infertilidad, entre otras. También se ha asociado la deficiencia materna de vitamina D en la génesis de patologías postnatales. Además, muchas de estas patologías se producirían por alteraciones moleculares, principalmente relacionadas con su metabolismo y con polimorfismos del receptor VCR. La vitamina D se considerara una hormona, puede ser sintetizada en la piel a partir 7-dehidrocolesterol mediante radiación ultravioleta B. Su metabolismo es complejo e implica la interacción de diversos factores en su incorporación y formación final de calcitriol, su forma activa. Para ejercer su efecto requiere de la activación del receptor VDR en la célula blanco, el cual a su vez activa secuencias de genes específicos con funciones diversas, a través de secuencias promotoras del ADN denominadas elementos de respuesta de vitamina D (VDRE). Muchos tejidos presentan el receptor VDR y enzimas necesarias para su metabolismo, por lo cual el espectro de acción de la vitamina D es muy amplio, así como la variedad de patologías que produce. Esta revisión de vitamina D, está centrada principalmente en los aspectos moleculares de su metabolismo y su rol en la génesis de enfermedades "no clásicas", producto de su disminución o alteración de su metabolismo.

Vitamin D has traditionally been associated with bone metabolism, however it exerts different functions in various tissues of the body that possess the vitamin D (VCR) receptor and they are susceptible to its effect. Decreased vitamin D has also been associated with "nonclassical" diseases such as hypertension, metabolic syndrome, insulin resistance, diabetes, development of some cancers, lung disorders,autoimmunity and infertility, among others. Maternal vitamin D deficiency has been associated in the genesis of postnatal diseases. Further, many of these pathologies are produced by molecular alterations, mainly related to metabolism and receptor polymorphisms VCR. Vitamin D is considered a hormone, can be synthesized in the skin from 7-dehydrocholesterol by ultraviolet radiation B. The metabolism is complex and involves the interaction of several factors in its incorporation and final formation of calcitriol, the active form. To produce its effect requires activation of VDR receptor on the target cell, which activates specific gene sequences with different functions, through DNA promoter sequences in identified vitamin D response elements (VDRE).Many tissues have the VDR receptor and enzymes necessary for metabolism, so the spectrum of vitamin Daction is very broad in the variety of pathologies produced. This review of vitamin D focuses primarily on the molecular aspects of its metabolism and its role in the genesis of "nonclassical", diseases, product of its reduction or alteration of metabolic diseases.

Roles of the Taql and Bsml vitamin D receptor gene polymorphisms in hospital mortality of burn patients

OBJECTIVE: The aim of this study was to evaluate the roles of the Taql and Bsml vitamin D receptor gene polymorphisms in hospital mortality of burn patients. METHODS: In total, 105 consecutive burn injury patients over 18 years in age who were admitted to the Burn Unit of Bauru State Hospital from January to December 2013 were prospectively evaluated. Upon admission, patient demographic information was recorded and a blood sample was taken for biochemical analysis to identify the presence of the Taql(rs731236) and Bsml(rs1544410) polymorphisms. All of the patients were followed over their hospital stay and mortality was recorded. RESULTS: Eighteen of the patients did not sign the informed consent form, and there were technical problems with genotype analysis for 7 of the patients. Thus, 80 patients (mean age, 42.5±16.1 years) were included in the final analysis. In total, 60% of the patients were male, and 16.3% died during the hospital stay. The genotype frequencies for the Taql polymorphism were 51.25% TT, 41.25% TC and 7.50% CC; for the Bsml polymorphism, they were 51.25% GG, 42.50% GA and 6.25% AA. In logistic regression analysis, after adjustments for age, gender and total body surface burn area, there were no associations between the Taql (OR: 1.575; CI95%: 0.148-16.745; p=0.706) or Bsml (OR: 1.309; CI95%: 0.128-13.430; p=0.821) polymorphisms and mortality for the burn patients. CONCLUSIONS: Our results suggest that the Taql and Bsml vitamin D receptor gene polymorphisms are not associated with hospital mortality of burn patients.

Efecto de los medicamentos antiepilépticos en el metabolismo de la vitamina D y el impacto negativo relacionado al déficit / Effect of antiepileptic drugs in the metabolism of vitamin D and negative impact related to the deficit

Resumen: la alteración en el metabolismo de la vitamina D ha ido creciendo en importancia hasta considerarse un problema de salud pública. Cada vez son más frecuentes las etiologías relacionadas al déficit de la vitamina D y con consecuencias a largo plazo, lo que hace necesario conocer no sólo las bases moleculares del metabolismo de la vitamina D, con especial atención en la participación de las enzimas de la familia del citocromo P450, sino la descripción de las vías metabólicas, la interacción con el receptor específico, las acciones genómicas y no genómicas, sus resultados en el metabolismo óseo y las acciones extra esqueléticas. Además, la acción directa de los antiepilépticos sobre las enzimas de la citocromo P450 y su efecto negativo sobre los niveles de la vitamina D y el metabolismo óseo. Esta revisión pretende brindar las bases que permitan extrapolar estos conceptos a la práctica clínica e identificar los pacientes con riesgo de hipovitaminosis D debido al uso crónico de antiepilépticos que requieren una conducta terapéutica. Es necesario tener presente que en la actualidad no hay un protocolo clínico universal sobre el seguimiento de estos pacientes incluso con la mejoría en el acceso a recursos diagnósticos.

Abstract: alteration in vitamin D metabolism has been growing in importance until be considered a heart public problem. Increasingly are more frequent the etiologies related to vitamin D deficiency and the long-term effects, which making necessary to know not only the molecular basic of vitamin D metabolism, with special attention to the parcipation of cytochrome p450 family enzymes, but also the descrition of the metabolic pathways, interaction with the specific receptor, genomic and non-genomic actions, result in bone metabolism and extraskeletal actions. In addition, the direct action of antiepileptic drugs on cytochrome p450 enzimes and their negative effects on vitamin D levels and bone metabolism. this review aims provide the basic that allow to extrapolate these concepts to clinical practice and identify patients at risk of vitamin D deficiency due to the chronically use antiepileptic drugs thal requisre therapeutic conduct. It should be remembered that currently there is no universal protocol on clinical monitoring of these patients even with the improvement in acess to diagnostic resources.

Estudo da deficiência de vitamina D no modelo de isquemia/reperfusão renal em ratos / Study of Vitamin D deficiency in rats submitted to renal ischemia/reperfusion

A deficiência de vitamina D (dVD) aumenta o risco de morte em pacientes hospitalizados. A injúria de isquemia/reperfusão renal (Isq) ativa vias de necrose e/ou apoptose e proliferação celular. A injúria renal aguda (IRA) induz a ativação de inibidores do ciclo celular, incluindo a p21, uma inibidora de kinase dependente de ciclina, a qual possui efeito protetor na IRA. A p21 é um alvo genômico da 25-hidroxivitamina D [25 (OH) D], a qual, atuando através de receptores de vitamina D (VDRs), possui efeitos imunomoduladores potentes e antiproliferativos, sugerindo a participação deste hormônio na fisiopatologia da doença renal. Desta forma, o objetivo deste estudo foi verificar a participação da deficiência de vitamina D no modelo de isquemia/reperfusão renal em ratos. Foram utilizados ratos Wistar que foram divididos em quatro grupos: controle (C), animais que receberam dieta padrão por 30 dias; dVD, animais que receberam dieta livre de vitamina D por 30 dias; Isq, animais que receberam dieta padrão por 30 dias e no 28º dia foram submetidos ao insulto de isquemia/reperfusão em ambos os rins por 45 minutos; e dVD+Isq, animais que receberam dieta livre de vitamina D por 30 dias e no 28º dia foram submetidos ao insulto de isquemia/reperfusão em ambos os rins por 45 minutos. Ao final dos 30 dias e após 48 horas da realização da isquemia/reperfusão, os animais foram submetidos à eutanásia e amostras de sangue, urina e tecido renal foram coletados para o estudo dos mecanismos de lesão renal. A injúria renal aguda associada à deficiência de vitamina D levou a uma queda da filtração glomerular e aumento da proteinúria; aumento da relação peso renal/peso corporal, sugerindo maior proliferação e hipertrofia; induziu uma diminuição na ativação dos receptores de vitamina D e da expressão da proteína p21 e aumento da expressão de caspase-3; observou-se déficit de concentração urinária com diminuição da expressão da AQP2; e um maior dano morfológico caracterizado pela análise...

Vitamin D deficiency (VDD) increases the risk of death in hospitalized patients. Ischemia/reperfusion injury activates pathways of necrosis and/or apoptosis and cell proliferation. Acute kidney injury (AKI) induces the activation of cell cycle inhibitors, including p21, an inhibitor of cyclin-dependent kinase, which has a protective effect on the IRA. The p21 is a genomic target of 25-hydroxyvitamin D [ 25 (OH) D], which, acting through vitamin D receptors (VDRs), has potent antiproliferative and immunomodulatory effects, suggesting the involvement of this hormone in the pathophysiology of renal disease. Thus, the aim of this study was to assess the role of vitamin D deficiency in rats submitted to renal ischemia/reperfusion. Wistar rats were divided into four groups: control (C), animals that received a standard diet for 30 days; VDD, animals that received vitamin D-free diet for 30 days; IRI, animals that received standard diet for 30 days and on day 28 were subjected to the ischemia/reperfusion insult (IRI) in both kidneys for 45 minutes; and VDD+IRI, animals that received vitamin D-free diet for 30 days and on day 28 were subjected to the IRI in both kidneys for 45 minutes. At the end of 30 days and 48 hours after the IRI insult, the animals were euthanized and samples of blood, urine and kidney tissue were collected to study the mechanisms of renal injury. Acute kidney injury associated with vitamin D deficiency led to a decrease in glomerular filtration rate and increased proteinuria; increased relative kidney weight/body weight, suggesting greater proliferation and hypertrophy; induced a decrease in the activation of vitamin D receptors and the p21 protein expression and, increased caspase-3 expression; renal concentration impairment with decreased AQP2 expression, as well as greater morphological damage characterized by interstitial area analysis and presence of tubular necrosis. Our data showed that altering the levels of p21 in...