Dataset Information

The metabolism of 1,25(OH)₂D₃ in clinical and experimental kidney disease.

ABSTRACT: Chronic kidney disease (CKD) results in calcitriol deficiency and altered vitamin D metabolism. The objective of this study was to assess the 24-hydroxylation-mediated metabolism of 25(OH)D₃ and 1,25(OH)₂D₃ in a cross-sectional analysis of participants with a range of kidney function assessed by precise measured GFR (mGFR) (N = 143) and in rats with the induction and progression of experimental kidney disease. Vitamin D metabolites were assessed with LC-MS/MS. Circulating measures of 24-hydroxylation of 25(OH)D₃ (24,25(OH)₂D₃:25(OH)D₃) precisely decreased according to mGFR in humans and progressively in rats with developing CKD. In contrast, the 1,24,25(OH)3D3: 1,25(OH)₂D₃ vitamin D metabolite ratio increased in humans as the mGFR decreased and in rats with the induction and progression of CKD. Human participants taking cholecalciferol had higher circulating 1,24,25(OH)₃D₃, despite no increase of 1,25(OH)₂D₃. This first report of circulating 1,24,25(OH)₃D₃ in the setting of CKD provides novel insight into the uniquely altered vitamin D metabolism in this setting. A better understanding of the uniquely dysfunctional catabolic vitamin D profile in CKD may guide more effective treatment strategies. The potential that 24-hydroxylated products have biological activity of is an important area of future research.

SUBMITTER: Turner ME

PROVIDER: S-EPMC9240002 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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The metabolism of 1,25(OH)2D3 in clinical and experimental kidney disease.

Turner Mandy E ME Rowsell Tyler S TS White Christine A CA Kaufmann Martin M Norman Patrick A PA Neville Kathryn K Petkovich Martin M Jones Glenville G Adams Michael A MA Holden Rachel M RM

Scientific reports 20220628 1

Chronic kidney disease (CKD) results in calcitriol deficiency and altered vitamin D metabolism. The objective of this study was to assess the 24-hydroxylation-mediated metabolism of 25(OH)D3 and 1,25(OH)2D3 in a cross-sectional analysis of participants with a range of kidney function assessed by precise measured GFR (mGFR) (N = 143) and in rats with the induction and progression of experimental kidney disease. Vitamin D metabolites were assessed with LC-MS/MS. Ci ...[more]

PMID: 35764669

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Project description:Background and purposeThere is sufficient evidence to support vitamin D's noncalcemic effects and the role of vitamin D deficiency in the development of a wide range of neurological disorders. This study aimed to evaluate whether serum 25(OH)D and 1,25(OH) 2 D could be used as biomarkers to differentiate between healthy subjects (HS), multiple system atrophy (MSA) and Parkinson's disease (PD) patients of both genders.MethodsA total of 107 subjects were included in this study, divided into three groups: 1- HS (n = 61), 2- MSA patients (n = 19), and 3- PD patients (n = 27). The patients were assessed using UMSARS II, UPDRS III, H&Y, MMSE and MoCA rating scales. The levels of 25(OH)D and 1,25(OH) 2 D in serum were determined using the radioimmunoassay technique.ResultsThe levels of 25(OH)D and 1,25(OH) 2 D in HS were 26.85 +/- 7.62 ng/mL and 53.63 +/- 13.66 pg/mL respectively. 25(OH)D levels were lower in both MSA and PD by 61% and 50%, respectively (P = 0.0001 vs. HS). 1,25(OH) 2 D levels were lower in MSA by 29%(P = 0.001 vs HS). There was a correlation between 25(OH)D and 1,25(OH) 2 D in MSA and PD, but not in HS. 1,25(OH) 2 D regressed with MMSE (β = 0.476, P = 0.04, R 2 = 0.226) in MSA, and with UPDRS III (β = -0.432, P = 0.024, R 2 = 0.187) and MoCA (β = 0.582, P = 0.005,R 2 = 0.279) in PD. 25(OH)D displayed considerable differentiative strength between HS and MSA (Wald = 17.123, OR = 0.586, P = 0.0001; AUC = 0.982, sensitivity and Youden index = 0.882, P = 0.0001) and PD (Wald = 18.552, OR = 0.700, P = 0.0001; AUC = 0.943, sensitivity = 0.889, YI = 0.791, P = 0.0001). 1,25(OH) 2 D distinguished MSA from PD (Wald 16.178, OR = 1.117, P = 0.0001; AUC = 0.868, sensitivity = 0.926, Youden index =0.632, P = 0.0001). H&Y exhibited the highest sensitivity, AUC, and significant distinguishing power between MSA and PD.ConclusionsSerum 25(OH)D and 1,25(OH) 2 D could be useful biomarkers for MSA and PD. 25(OH)D and H&Y provided the highest sensitivity and group classification characteristics.

Project description:Background and aimsVitamin D exists as an inactive 25-hydroxyvitamin D (25(OH)D) in the bloodstream, which is converted to active 1,25-dihydroxyvitaminD (1,25(OH)2D) in target tissues. Cohort studies reporting cardiovascular disease among individuals with low vitamin D are inconsistent and solely measure 25(OH)D. Psoriasis, a chronic inflammatory disease, is a vitamin D deficient state and is associated with increased cardiovascular disease risk. While serum 25(OH)D is routinely measured, we hypothesized that measurement of 1,25(OH)2D in psoriasis may perform better than 25(OH)D in capturing cardiovascular risk.MethodsConsecutive psoriasis patients (N = 122) at baseline underwent FDG PET/CT and CCTA scans to measure visceral adipose volume, aortic vascular uptake of FDG, and coronary plaque burden respectively. Blood levels of both 1,25(OH)2D and 25(OH)D were measured by chemiluminescence (LIAISON XL DIaSorin, Stillwater, MN).ResultsThe psoriasis cohort was middle-aged (mean ± SD: 49.6 ± 13.0), predominantly male (n = 71, 58%), in majority Caucasians (n = 98, 80%), and had moderate-to-severe skin disease [psoriasis area severity index score, PASI score, med.(iqr)5.5 (3.2-10.7)], with almost one-fourth of the cohort on biologic psoriasis therapy for skin disease management (n = 32, 27%) at baseline. Interestingly, serum levels of 1,25(OH)2D but not 25(OH)D were found to be inversely associated with visceral adipose, a marker of cardiometabolic risk in fully adjusted models (β = - 0.43, p = 0.026 and β = -0.26 p = 0.13). Similarly, we found an inverse relationship between 1,25(OH)2D, but not 25(OH)D, and aortic vascular uptake of FDG independent of traditional risk factors (β = -0.19, p = 0.01). Finally, we found that serum 1,25(OH)2D, but not 25(OH)D, was inversely associated with non-calcified coronary plaque burden, as measured by CCTA independent of traditional risk factors (β = -0.18, p = 0.03).ConclusionsIn conclusion, we demonstrate that low 1,25(OH)2D levels were associated with visceral adipose volume, vascular uptake of FDG and coronary plaque burden independent of traditional risk factors, suggesting that 1,25(OH)2D may better capture the cardiometabolic risk associated with vitamin D deficient states.

Project description:Doxorubicin (DOX), as a chemotherapy agent with marked therapeutic effect, can be used to treat certain types of cancer such as leukemia, lymphoma and breast cancer. However, the toxic effects of DOX on cardiomyocytes limit its clinical application. Oxidative stress has been documented to serve a pivotal role in DOX-induced cardiomyopathy. Previous studies have reported that 1,25(OH)2D3 has antioxidant and anti-inflammatory effects and can inhibit the renin-angiotensin system. However, the effects of 1,25(OH)2D3 on the pathophysiological processes of DOX-induced cardiomyopathy and its mechanisms remain poorly understood. To investigate these potential effects, C57BL/6J mice were used to construct a DOX-induced cardiomyopathy model and treated with 1,25(OH)2D3. At 4 weeks after the first injection of DOX, cardiac function and myocardial injury were evaluated by echocardiograph and ELISA. Masson's trichrome staining and RT-qPCR were used to assess myocardial fibrosis, and immunohistochemistry and western blotting were performed to analyze expression levels of inflammation and oxidative stress, and the NLRP3 inflammasome pathway. ChIP assay was used to assess the effects of 1,25(OH)2D3 on histone modification in the NLRP3 and Nrf2 promoters. The results showed that 1,25(OH)2D3 treatment increased LVEF and LVFS, reduced serum levels of BNP and cTnT, inhibited the collagen deposition and profibrotic molecular expression, and downregulated the levels of inflammatory cytokines in DOX-induced cardiomyopathy. ROS and antioxidant indices were also ameliorated after 1,25(OH)2D3 treatment. In addition, 1,25(OH)2D3 was found to inhibit the NLRP3 inflammasome and KEAP-Nrf2 pathways through regulation of the levels of H3K4me3, H3K27me3 and H2AK119Ub in the NLRP3 and Nrf2 promoters. In conclusion, the present study demonstrated that 1,25(OH)2D3 regulated histone modification in the NLRP3 and Nrf2 promoters, which in turn inhibits the activation of NLRP3 inflammasome and oxidative stress in cardiomyocytes, alleviating DOX-induced cardiomyopathy. Therefore, 1,25(OH)2D3 may be a potential drug candidate for the treatment of DOX-induced cardiomyopathy.

Dataset Information

The metabolism of 1,25(OH)₂D₃ in clinical and experimental kidney disease.

Publications

The metabolism of 1,25(OH)<sub>2</sub>D<sub>3</sub> in clinical and experimental kidney disease.

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