Extrarenal Vitamin D Activation and Interactions Between Vitamin D<sub>2</sub>, Vitamin D<sub>3</sub>, and Vitamin D Analogs

Jones, Glenville

doi:10.1146/annurev-nutr-071812-161203

Cited by 116 publications

(114 citation statements)

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“…We hypothesize that the discordant associations of 25(OH)D and 1,25(OH) 2 D with increased albuminuria may be explained by autocrine/paracrine activation of 25(OH)D. This is supported by the fact that 1a-hydroxylase is expressed by various cell types other than tubular epithelial cells, including podocytes, with subsequent local activation of VDRs (44)(45)(46) and circulating levels of 25(OH)D exceeding 1,25(OH) 2 D by approximately 400-fold in our study.…”

Section: Discussionmentioning

confidence: 96%

Plasma Vitamin D Level and Change in Albuminuria and eGFR According to Sodium Intake

Keyzer¹,

Lambers-Heerspink²,

Joosten

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Low circulating 25-hydroxyvitamin D [25(OH)D] and high sodium intake are both associated with progressive albuminuria and renal function loss in CKD. Both vitamin D and sodium intake interact with the renin-angiotensin-aldosterone system. We investigated whether plasma 25(OH)D or 1,25-dihydroxyvitamin D [1,25(OH) 2 D] is associated with developing increased albuminuria or reduced renal function and whether these associations depend on sodium intake.Design, setting, participants, & measurements Baseline plasma 25(OH)D and 1,25(OH) 2 D were measured by liquid chromatography tandem mass spectrometry, and sodium intake was assessed by 24-hour urine collections in the general population-based Prevention of Renal and Vascular End-Stage Disease cohort (n=5051). Two primary outcomes were development of urinary albumin excretion .30 mg/24 h and eGFR (creatinine/cystatin C-based CKD Epidemiology Collaboration) ,60 ml/min per 1.73 m 2 . Participants with CKD at baseline were excluded. In Cox regression analyses, we assessed associations of vitamin D with developing increased albuminuria or reduced eGFR and potential interaction with sodium intake.Results During a median follow-up of 10.4 (6.2-11.4) years, 641 (13%) participants developed increased albuminuria, and 268 (5%) participants developed reduced eGFR. Plasma 25(OH)D was inversely associated with increased albuminuria (fully adjusted hazard ratio [HR] per SD higher, 0.86; 95% confidence interval [95% CI], 0.78 to 0.95; P=0.003) but not reduced eGFR (HR, 0.99; 95% CI, 0.87 to 1.12; P=0.85). There was interaction between 25(OH)D and sodium intake for risk of developing increased albuminuria (P interaction =0.03). In participants with high sodium intake, risk of developing increased albuminuria was inversely associated with 25(OH)D (lowest versus highest quartile: adjusted HR, 1.81; 95% CI, 1.20 to 2.73, P,0.01), whereas this association was nonsignificant in participants with low sodium intake (HR, 1.29; 95% CI, 0.94 to 1.77; P=0.12). Plasma 1,25(OH) 2 D was not significantly associated with increased albuminuria or reduced eGFR.Conclusions Low plasma 25(OH)D is associated with higher risk of developing increased albuminuria, particularly in individuals with high sodium intake, but not of developing reduced eGFR. Plasma 1,25(OH)2D is not associated with risk of developing increased albuminuria or reduced eGFR.

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Section: Discussionmentioning

confidence: 96%

Plasma Vitamin D Level and Change in Albuminuria and eGFR According to Sodium Intake

Keyzer¹,

Lambers-Heerspink²,

Joosten

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…The metabolic pathway of this endogenously and exogenously derived vitamin D through its various hydroxylation and oxidation events was described comprehensively previously (1)(2)(3). Recently, it was discovered that vitamin D can alternatively be metabolized through a 3 epimerization pathway that parallels the standard metabolic pathway (4,5) and thus accounts for the presence of epimerized vitamin D metabolites in human sera.…”

Section: Introductionmentioning

confidence: 99%

The 3 Epimer of 25-Hydroxycholecalciferol Is Present in the Circulation of the Majority of Adults in a Nationally Representative Sample and Has Endogenous Origins

Cashman

Kinsella

Walton

et al. 2014

The Journal of Nutrition

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Fundamental knowledge gaps in relation to the 3 epimer of 25-hydroxycholecalciferol [3-epi-25(OH)D₃] limit our understanding of its relevance for vitamin D nutrition and health. The aims of this study were to characterize the 3-epi-25(OH)D₃ concentrations in a nationally representative sample of adults and explore its determinants. We also used data from a recent randomized controlled trial (RCT) of supplemental cholecalciferol (vitamin D₃) conducted in winter in older adults to directly test the impact of changes in vitamin D status on serum 3-epi-25(OH)D3 concentrations. Serum 25-hydroxycholecalciferol [25(OH)D₃] and 3-epi-25(OH)D₃ concentrations (via LC-tandem mass spectrometry) from our vitamin D₃ RCT in adults (aged ≥50 y) and data on dietary, lifestyle, and biochemical characteristics of participants of the recent National Adult Nutrition Survey in Ireland (aged 18-84 y; n = 1122) were used in the present work. In the subsample of participants who had serum 3-epi-25(OH)D₃ concentrations greater than the limit of quantification (n = 1082; 96.4%), the mean, 10th, 50th (median), and 90th percentile concentrations were 2.50, 1.05, 2.18, and 4.30 nmol/L, respectively, whereas the maximum 3-epi-25(OH)D₃ concentration was 15.0 nmol/L. A regression model [explaining 29.9% of the variability in serum 3-epi-25(OH)D₃] showed that age >50 y, vitamin D supplement use, dietary vitamin D, meat intake, season of blood sampling, and sun exposure habits were significant positive determinants, whereas increasing waist circumference and serum 25-hydroxyergocalciferol concentration were significant negative determinants. The RCT data showed that mean serum 25(OH)D₃ and 3-epi-25(OH)D₃ concentrations increased (49.3% and 42.1%, respectively) and decreased (-28.0% and -29.1%, respectively) significantly (P < 0.0001) with vitamin D₃ (20 μg/d) and placebo supplementation, respectively, over 15 wk of winter. In conclusion, we provide data on serum 3-epi-25(OH)D₃ in a nationally representative sample of adults. Our combined observational and RCT data might suggest that both dietary supply and dermal synthesis of vitamin D₃ contribute to serum 3-epi-25(OH)D₃ concentration.

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“…This form is subsequently hydroxylated, predominantly in the kidney, to its active metabolite, 1,25-dihydroxyvitamin D [1,25(OH) 2 D]. Importantly, the enzyme that catalyzes this latter reaction, CYP27B1, is also expressed at several extra-renal sites (2,3), including dermal keratinocytes (4). It is thought that locally produced 1,25(OH) 2 D may have autocrine or paracrine functions.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D signaling regulates oral keratinocyte proliferation in vitro and in vivo

Yuan

Valiyaparambil

Woods

et al. 2014

International Journal of Oncology

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The secosteroidal hormone 1,25-dihyroxyvitamin D [1,25(OH)2D3] and its receptor, the vitamin D receptor (VDR), are crucial regulators of epidermal proliferation and differentiation. However, the effects of 1,25(OH)2D3-directed signaling on oral keratinocyte pathophysiology have not been well studied. We examined the role of 1,25(OH)2D3 in regulating proliferation and differentiation in cultured oral keratinocytes and on the oral epithelium in vivo. Using lentiviral-mediated shRNA to silence VDR, we generated an oral keratinocyte cell line with stable knockdown of VDR expression. VDR knockdown significantly enhanced proliferation and disrupted calcium- and 1,25(OH)2D3-induced oral keratinocyte differentiation, emphasizing the anti-proliferative and pro-differentiation effects of 1,25(OH)2D3 in oral keratinocytes. Using vitamin D3-deficient diets, we induced chronic vitamin D deficiency in mice as evidenced by decreased serum 25-hydroxyvitamin D (25OHD) concentrations. The vitamin D-deficient mice manifested increased proliferation of the tongue epithelium, but did not develop any morphological or histological abnormalities in the oral epithelium, suggesting that vitamin D deficiency alone is insufficient to alter oral epithelial homeostasis and provoke carcinogenesis. Immunohistochemical analyses of human and murine oral squamous cell carcinomas showed increased VDR expression. Overall, our results provide strong support for a crucial role for vitamin D signaling in oral keratinocyte pathophysiology.

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Extrarenal Vitamin D Activation and Interactions Between Vitamin D₂, Vitamin D₃, and Vitamin D Analogs

Cited by 116 publications

References 104 publications

Plasma Vitamin D Level and Change in Albuminuria and eGFR According to Sodium Intake

Plasma Vitamin D Level and Change in Albuminuria and eGFR According to Sodium Intake

The 3 Epimer of 25-Hydroxycholecalciferol Is Present in the Circulation of the Majority of Adults in a Nationally Representative Sample and Has Endogenous Origins

Vitamin D signaling regulates oral keratinocyte proliferation in vitro and in vivo

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Extrarenal Vitamin D Activation and Interactions Between Vitamin D2, Vitamin D3, and Vitamin D Analogs

Cited by 116 publications

References 104 publications

Plasma Vitamin D Level and Change in Albuminuria and eGFR According to Sodium Intake

Plasma Vitamin D Level and Change in Albuminuria and eGFR According to Sodium Intake

The 3 Epimer of 25-Hydroxycholecalciferol Is Present in the Circulation of the Majority of Adults in a Nationally Representative Sample and Has Endogenous Origins

Vitamin D signaling regulates oral keratinocyte proliferation in vitro and in vivo

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Extrarenal Vitamin D Activation and Interactions Between Vitamin D₂, Vitamin D₃, and Vitamin D Analogs