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- Checkpoint kinase Chk2 controls renal Cyp27b1 expression, calcitriol formation, and calcium-phosphate metabolism. [JOURNAL ARTICLE]
- Pflugers Arch 2014 Oct 17.
Checkpoint kinase 2 (Chk2) is the main effector kinase of ataxia telangiectasia mutated (ATM) and responsible for cell cycle regulation. ATM signaling has been shown to upregulate interferon-regulating factor-1 (IRF-1), a transcription factor also expressed in the kidney. Calcitriol (1,25 (OH)2D3), a major regulator of mineral metabolism, is generated by 25-hydroxyvitamin D 1α-hydroxylase in the kidney. Since 25-hydroxyvitamin D 1α-hydroxylase expression is enhanced by IRF-1, the present study explored the role of Chk2 for calcitriol formation and mineral metabolism. Chk2-deficient mice (chk2 (-/-)) were compared to wild-type mice (chk2 (+/+)). Transcript levels of renal 25-hydroxyvitamin D 1α-hydroxylase, Chk2, and IRF-1 were determined by RT-PCR; Klotho expression by Western blotting; bone density by μCT analysis; serum or plasma 1,25 (OH)2D3, PTH, and C-terminal FGF23 concentrations by immunoassays; and serum, fecal, and urinary calcium and phosphate concentrations by photometry. The renal expression of IRF-1 and 25-hydroxyvitamin D 1α-hydroxylase as well as serum 1,25 (OH)2D3 and FGF23 levels were significantly lower in chk2 (-/-) mice compared to chk2 (+/+) mice. Plasma PTH was not different between the genotypes. Renal calcium and phosphate excretion were significantly higher in chk2 (-/-) mice than in chk2 (+/+) mice despite hypophosphatemia and normocalcemia. Bone density was not different between the genotypes. We conclude that Chk2 regulates renal 25-hydroxyvitamin D 1α-hydroxylase expression thereby impacting on calcium and phosphate metabolism.
- Epicardial adipose tissue inflammation is related to vitamin D deficiency in patients affected by coronary artery disease. [JOURNAL ARTICLE]
- Nutr Metab Cardiovasc Dis 2014 Sep 19.
Alterations in epicardial adipose tissue (EAT) biology (i.e. increased fat thickness and inflammation) have been described in coronary artery disease (CAD) patients. In addition to its classic role in the regulation of calcium-phosphate homeostasis, vitamin D may exert immune-regulatory and anti-inflammatory effects. Whether EAT inflammation may be linked to vitamin D deficiency is still unknown. In the present study we evaluated plasma 25-hydroxycholecalciferol (25OHD) level in CAD patients and its relationship with EAT ability to locally metabolize vitamin D, EAT expression of inflammation-related molecules and EAT thickness.Plasma 25OHD level was quantified by an immunoluminometric assay. EAT expression of inflammation-related molecules (MCP-1, PTX3, TNFα, IL-6, adiponectin), vitamin D receptor (VDR), CYP27B1 (25OHD-activating enzyme) and CYP24A1 (1,25-dihydroxycholecalciferol-metabolizing enzyme) was performed by microarray. EAT thickness was quantified by echocardiography. Median plasma 25OHD level was 10.85 ng/mL and 83% of CAD patients displayed 25OHD level below 20 ng/mL. At decreasing plasma 25OHD concentration, we observed a down-regulation in CYP27B1 and CYP24A1 level and an increased expression of VDR and pro-inflammatory cytokines (MCP-1, PTX3, TNFα, IL-6) at EAT level. No correlation was observed between plasma 25OHD level and EAT thickness.Our data suggest an increased activation of inflammatory pathways at EAT level possibly related to systemic and local vitamin D deficiency in CAD patients. Whether maintaining an optimal vitamin D status may be helpful to reduce EAT inflammation and to prevent CAD and its progression needs further investigation.
- Increased oxygen consumption observed in phorbol 12-myristate 13-acetate stimulated human cultured promonocytic U937 cell lines treated with calcitriol and retinoic acid. [Journal Article]
- Asian Pac J Trop Med 2014 Sep.:S272-7.
To investigate the effect of phorbol 12-myristate 13-acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (FMLP) on oxygen consumption of differentiated and non-differentiated immune cell lines by retinoic acid and calcitriol treatment which might be useful in subsequent elicitation of immunological action during immunosuppressive states.PMA and FMLP were used to artificially stimulate reactive oxygen production in cultured promonocytic U937 cell line. Paralleled samples of the cultured cells were separately prepared with calcitriol (1, 25- dihydroxyvitamin D3) and retinoic acid followed by a 72-hour incubation period. The rate of respiratory burst was measured using the Clark oxygen electrode.The average increase in cell concentrations per mL observed was significantly higher in retinoic acid-treated cells (9×10(6) cells/mL) when compared with calcitriol-treated samples (4×10(6) cells/mL). There was a marked increase in oxygen consumption of the calcitriol-treated cell lines against the retinoic acid-treated ones. Exposure of differentiated U937 cells to PMA and FMLP increased significantly (P<0.05) in their oxygen consumption when compared with the control. PMA calcitriol-treated cells resulted in 55% oxygen consumption more than the control while FMLP oxygen consumption increased 78% by comparison with the control.The result demonstrated that calcitriol may serve as a physiological promoter of normal differentiation of precursor cells which may exert an immunological action. This effect could elicit a marker potential and increase immune cell activity of the host especially in immunosuppressed diseased states.
- Cinacalcet administration by gastrostomy tube in a child receiving peritoneal dialysis. [Journal Article]
- J Pediatr Pharmacol Ther 2014 Jul; 19(3):202-5.
A 2-year-old male with chronic kidney disease with secondary hyperparathyroidism developed hypercalcemia while receiving calcitriol, without achieving a serum parathyroid hormone concentration within the goal range. Cinacalcet 15 mg (1.2 mg/kg), crushed and administered via gastrostomy tube, was added to the patient's therapy. This therapy was effective in achieving targeted laboratory parameters in our patient despite instructions in the prescribing information that cinacalcet should always be taken whole.
- The origin and metabolism of vitamin D in rainbow trout. [JOURNAL ARTICLE]
- J Steroid Biochem Mol Biol 2014 Oct 9.
An explanation for the origin and the high concentration of vitamin D (cholecalciferol) in some species of fish is still not apparent. Because fish may live in deep water and may, thus, not be exposed to solar ultraviolet (UV) light, it is commonly assumed that vitamin D found in their livers and adipose tissue has been derived from a food chain, originating in zooplankton exposed to UV light at the water surface. To investigate the metabolism and possible origin of vitamin D in fish, rainbow trout were reared from eggs, in the absence of light, and were fed a vitamin D-free diet. When small quantities of radioactively-labelled vitamin D were injected or fed to these trout, much of the radioactivity was found as excreted metabolites in bile. Hence, even when they are vitamin D deficient, trout vigorously catabolise and excrete exogenous vitamin D. The main vitamin D metabolite found in plasma of non-deficient trout was 1,25-dihydroxycholecalciferol [1,25(OH)2D3]. This was produced in the liver by an enzyme process that was strongly stimulated in vitamin D deficiency. When vitamin D was fed for several weeks to vitamin D-deficient trout, plasma 1,25(OH)2D3 levels rose to 180pg/ml and the fish became hypercacemic. When vitamin D-deficient fish were inadvertently exposed to 60W incandescent light for 24h, they became moribund and died. It was subsequently found that vitamin D-deficient trout can produce vitamin D in skin when exposed to blue light at wavelengths between 380 and 480nm. It is concluded that trout, like terrestrial vertebrates, produce 1,25(OH)2D3 as the functional form of vitamin D and that this has an effect on calcium homeostasis. Furthermore, vitamin D is formed in the skin of these fish by the photochemical action of visible light on 7-dehydrocholesterol. Elucidation of the physicochemical mechanism of this process requires further research.
- Oral manifestations of hyperparathyroidism secondary to familial hypophosphatemic rickets. [Journal Article]
- Pediatr Dent 2014; 36(5):422-4.
A 14-year-old male with familial hypophosphatemic rickets, being treated with oral phosphate and calcitriol therapy, presented to the Division of Pediatric Dentistry, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pa. A panoramic radiograph showed multifocal, multilocular lesions in the mandible leading to surgical exploration and biopsy. Histopathological evaluation of the largest lesion showed features consistent with central giant cell granuloma. Given the patient's history, hyperparathyroidism was suspected. Laboratory data showed an elevated parathyroid hormone of 152 pg/ml (normal range equals nine to 69). This confirmed the diagnosis of multiple brown tumors in the mandible associated with secondary hyperparathyroidism, which was attributed to high-dose phosphate treatment. After endocrinology consultation, calcitriol therapy was increased. Improvement of the patient's brown tumors is expected with medical therapy. The purpose of this case report was to raise awareness among pediatric dentists about the maxillofacial ramifications of secondary hyperparathyroidism.
- From Hypocalcemia to Hypercalcemia - An Unusual Clinical Presentation of a Patient with Permanent Post-Surgical Hypoparathyroidism. [JOURNAL ARTICLE]
- J Clin Endocrinol Metab 2014 Oct 10.:jc20143063.
Context: Hypercalcemia associated with lymphomas can be secondary to increased calcitriol [1,25(OH)2 vitamin D3], parathyroid hormone-related protein, or osteolytic metastases. Objective: Presentation of a case of calcitriol mediated hypercalcemia secondary to non-Hodgkin lymphoma (NHL), in a patient with post-surgical hypoparathyroidism. Design & setting: Single patient managed at a tertiary health care facility in the United States. Patient: A 55-year-old white woman had a total thyroidectomy and radioiodine ablation for a 3.5 cm follicular carcinoma. Surgery was complicated by permanent hypoparathyroidism treated with calcium, calcitriol, and cholecalciferol. For over 16 years she had no evidence of either residual thyroid tissue in the neck or metastasis. Her corrected serum calcium levels were appropriately maintained in the low-normal range. During a routine clinic visit she had mild hypercalcemia; calcium and cholecalciferol were reduced by 50%, while calcitriol was continued. Two weeks later she presented with nausea, abdominal pain, and multiple, rapidly enlarging cervical and axillary lymph nodes with elevated calcium and calcitriol. A Fluorine-18 Fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) scan and lymph node biopsy were diagnostic for NHL. Intervention: Calcium and calcitriol were stopped; hypercalcemia was corrected with IV fluids. Chemotherapy resulted in an excellent response within 7 weeks; calcitriol normalized and she developed recurrent hypocalcemia. A PET/CT at 7 weeks and 3 months after treatment documented near complete resolution of the lesions. Outcome & Result: Sixteen months after the treatment of lymphoma she remains free of disease and is on calcium, calcitriol and cholecalciferol. Conclusion: Clinicians should have a high index of suspicion for malignancy when patients presents with rapid and high elevations of serum calcium.
- Elevated serum 1,25(OH)2-vitamin D3 level attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in kl/kl mice. [Journal Article]
- Sci Rep 2014.:6563.
Previous studies have suggested that Klotho provides reno-protection against unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis (RTF). Because the existing studies are mainly performed using heterozygous Klotho mutant (HT) mice, we focused on the effect of UUO on homozygous Klotho mutant (kl/kl) mice. UUO kidneys from HT mice showed a significantly higher level of RTF and TGF-β/Smad3 signaling than wild-type (WT) mice, whereas both were greatly suppressed in kl/kl mice. Primary proximal tubular epithelial culture cells isolated from kl/kl mice showed no suppression in TGF-β1-induced epithelial mesenchymal transition (EMT) compared to those from HT mice. In the renal epithelial cell line NRK52E, a large amount of inorganic phosphate (Pi), FGF23, or calcitriol was added to the medium to mimic the in vivo homeostasis of kl/kl mice. Neither Pi nor FGF23 antagonized TGF-β1-induced EMT. In contrast, calcitriol ameliorated TGF-β1-induced EMT in a dose dependent manner. A vitamin D3-deficient diet normalized the serum 1,25 (OH)2 vitamin D3 level in kl/kl mice and enhanced UUO-induced RTF and TGF-β/Smad3 signaling. In conclusion, the alleviation of UUO-induced RTF in kl/kl mice was due to the TGF-β1 signaling suppression caused by an elevated serum 1, 25(OH)2 vitamin D3.
- The induction of C/EBPβ contributes to vitamin D inhibition of ADAM17 expression and parathyroid hyperplasia in kidney disease. [JOURNAL ARTICLE]
- Nephrol Dial Transplant 2014 Oct 7.
In secondary hyperparathyroidism (SHPT), enhanced parathyroid levels of transforming growth factor-α (TGFα) increase EGF receptor (EGFR) activation causing parathyroid hyperplasia, high parathyroid hormone (PTH) and also reductions in vitamin D receptor (VDR) that limit vitamin D suppression of SHPT. Since anti-EGFR therapy is not an option in human SHPT, we evaluated ADAM17 as a therapeutic target to suppress parathyroid hyperplasia because ADAM17 is required to release mature TGFα, the most potent EGFR-activating ligand.Computer analysis of the ADAM17 promoter identified TGFα and C/EBPβ as potential regulators of the ADAM17 gene. Their regulation of ADAM17 expression, TGFα/EGFR-driven growth and parathyroid gland (PTG) enlargement were assessed in promoter-reporter assays in A431 cells and corroborated in rat and human SHPT, using erlotinib as anti-EGFR therapy to suppress TGFα signals, active vitamin D to induce C/EBPβ or the combination.While TGFα induced ADAM17-promoter activity by 2.2-fold exacerbating TGFα/EGFR-driven growth, ectopic C/EBPβ expression completely prevented this vicious synergy. Accordingly, in advanced human SHPT, parathyroid ADAM17 levels correlated directly with TGFα and inversely with C/EBPβ. Furthermore, combined erlotinib + calcitriol treatment suppressed TGFα/EGFR-cell growth and PTG enlargement more potently than erlotinib in part through calcitriol induction of C/EBPβ to inhibit ADAM17-promoter activity, mRNA and protein. Importantly, in rat SHPT, the correction of vitamin D deficiency effectively reversed the resistance to paricalcitol induction of C/EBPβ to suppress ADAM17 expression and PTG enlargement, reducing PTH by 50%.In SHPT, correction of vitamin D and calcitriol deficiency induces parathyroid C/EBPβ to efficaciously attenuate the severe ADAM17/TGFα synergy, which drives PTG enlargement and high PTH.
- The novel role of TRPC6 in vitamin D ameliorating podocyte injury in STZ-induced diabetic rats. [JOURNAL ARTICLE]
- Mol Cell Biochem 2014 Oct 9.
Podocyte injury plays a critical role in the development and progression of diabetic nephropathy (DN). Over expression of TRPC6 on the podocytes has been revealed to cause podocyte injury in non-diabetic states. Besides, the emerging evidence from clinic revealed that vitamin D could reduce albuminuria and improve renal function, which was associated with podocyte protection. Our study aimed to investigate whether calcitriol ameliorating podocyte impairment is associated with regulation of the expression of TRPC6 in STZ-induced rats. Sprague-Dawley rats were randomly divided into three groups: normal control, DN, and DN treated with calcitriol (DN + VD); VD rats were treated with 0.1 μg/kg/d calcitriol by gavage. DN model rats were established by intraperitoneal injections of streptozocin. The rats were sacrificed after 18 weeks treatment. DN rats exhibited increased proteinuria accompanied by elevated TRPC6 expression. Treatment with calcitriol not only reduced proteinuria, but also normalized TRPC6 expression. Meanwhile, in DN rats, the expression of podocyte specific markers including nephrin and podocin was significantly decreased, accompanied by increased desmin, a marker of podocyte injury. Treatment with calcitriol reversed above changes. In addition, vitamin D receptor (VDR) was significantly decreased, whereas this reduction was attenuated by the calcitriol treatment. Moreover, TRPC6 was positively correlated with both 24 h urinary protein and desmin. In contrast, TRPC6 was negatively correlated with both VDR and nephrin expression in podocytes. Calcitriol can ameliorate podocyte injury, which is contributed by the inhibition of enhanced TRPC6 expression in the early stages of DN rats.