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PloS One 2019This study aimed to assess the renopreventive effect of enalapril and/or paricalcitol on streptozotocin (STZ) diabetes-induced nephropathy and to elucidate their...
This study aimed to assess the renopreventive effect of enalapril and/or paricalcitol on streptozotocin (STZ) diabetes-induced nephropathy and to elucidate their mechanisms of action through investigation of the effects on renal oxidative stress, antioxidant defense system and expressions of TNF-α, p53, caspase-3, and Bcl-2. Diabetes mellitus was induced in fasting male Wistar rats by single intraperitoneal injection of STZ (45 mg /kg b.w.) dissolved in citrate buffer (pH 4.5). Ten days after STZ injection, the diabetic rats were treated with enalapril (25 mg/l of drinking water) and/or paricalcitol (8 μg/kg b.w. per os) dissolved in 5% DMSO daily for 4 weeks. The obtained data revealed that the treatment of diabetic Wistar rats with enalapril and/or paricalcitol led to significant decreases in the elevated serum urea, uric acid, creatinine, sodium and potassium levels; thereby reflecting the improvement of the impaired kidney function. The deteriorated kidney lipid peroxidation, GSH content and GST and catalase activities in diabetic rats were significantly ameliorated as a result of treatment with enalapril and/or paricalcitol. The elevated fasting and post-prandial serum glucose levels and the lowered serum insulin and C-peptide levels were also improved. The treatment with enalapril and paricalcitol in combination was the most potent in decreasing the elevated serum glucose levels. Moreover, the treatment of diabetic rats successfully prevented the diabetes-induced histopathological deleterious changes of kidney and islets of Langerhans of pancreas. In association, the immunohistochemically detected pro-inflammatory cytokine, TNF-α, and apoptotic mediators, p53 and caspase-3, were remarkably decreased in kidney of diabetic rats as a result of treatment while the expression of anti-apoptotic protein Bcl-2 was increased. Based on these findings, it can be concluded that enalapril and paricalcitol alone or in combination can prevent STZ diabetes-induced nephropathy through amelioration of the glycemic state and antioxidant defense system together with the suppression of oxidative stress, inflammation and apoptosis. However, the treatment of diabetic rats with enalapril and paricalcitol in combination has no further significant improvement effects on renal function and damage when compared with enalapril or paclitaxel treated diabetic groups.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Caspase 3; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Ergocalciferols; Islets of Langerhans; Kidney; Male; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53
PubMed: 31527864
DOI: 10.1371/journal.pone.0214349 -
JBMR Plus Aug 2019FGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co-receptor Klotho, it modulates phosphate reabsorption and both 1α-hydroxylation... (Review)
Review
FGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co-receptor Klotho, it modulates phosphate reabsorption and both 1α-hydroxylation and 24-hydroxylation in the renal proximal tubules. The most common FGF23-mediated hypophosphatemia is X-linked hypophosphatemia (XLH), caused by mutations in the gene. FGF23-mediated forms of hypophosphatemia are characterized by phosphaturia and low or low-normal calcitriol concentrations, and unlike nutritional rickets, these cannot be cured with nutritional vitamin D supplementation. Autosomal dominant and autosomal recessive forms of FGF23-mediated hypophosphatemias show a similar pathophysiology, despite a variety of different underlying genetic causes. An excess of FGF23 activity has also been associated with a number of other conditions causing hypophosphatemia, including tumor-induced osteomalacia, fibrous dysplasia of the bone, and cutaneous skeletal hypophosphatemia syndrome. Historically phosphate supplementation and therapy using analogs of highly active vitamin D (eg, calcitriol, alfacalcidol, paricalcitol, eldecalcitol) have been used to manage conditions involving hypophosphatemia; however, recently a neutralizing antibody for FGF23 (burosumab) has emerged as a promising treatment agent for FGF23-mediated disorders. This review discusses the progression of clinical trials for burosumab for the treatment of XLH and its recent availability for clinical use. Burosumab may have potential for treating other conditions associated with FGF23 overactivity, but these are not yet supported by trial data. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
PubMed: 31485552
DOI: 10.1002/jbm4.10190 -
Laboratory Investigation; a Journal of... Dec 2019Liver cirrhosis is a life-threatening consequence of liver fibrosis. The aim of this study was to investigate the antifibrotic potential of clinically available vitamin... (Comparative Study)
Comparative Study
Liver cirrhosis is a life-threatening consequence of liver fibrosis. The aim of this study was to investigate the antifibrotic potential of clinically available vitamin D analogs compared to that of calcitriol in vitro and in vivo. Murine hepatic stellate cells, Kupffer cells, and human LX-2 cells were treated with vitamin D analogs, and the profibrotic behavior of these cells was studied. In vivo liver fibrosis was induced using CCl until measurable fibrosis was established. Animals were then treated with calcitriol and paricalcitol. Vitamin D and its analogs showed antifibrotic effects in vitro. Treatment with active vitamin D (calcitriol, CAL) and its analogs reduced the protein expression of α-smooth muscle actin (α-SMA) in mHSC. In human LX-2 cells alfacalcidol reduced transforming growth factor-β (TGF-β) induced platelet-derived growth factor receptor-β protein expression and contractility while paricalcitol (PCT), in its equipotent dose to CAL, reduced TGF-β induced α-SMA protein expression, and ACTA2 and TGF-β mRNA expression. No effects of a treatment with vitamin D and its analogs were observed in Kupffer cells. In vivo, PCT-treated mice had significantly lower calcium levels than CAL-treated mice. CAL and PCT reduced the hepatic infiltration of CD11b-positive cells and alanine transaminase levels, while PCT but not CAL significantly inhibited fibrosis progression, with a favorable side effect profile in the CCl model. We conclude that hypocalcemic vitamin D analogs should be considered in future studies investigating vitamin D for the treatment of liver fibrosis.
Topics: Animals; Calcitriol; Calcium; Carbon Tetrachloride; Cell Line; Drug Evaluation, Preclinical; Ergocalciferols; Hepatic Stellate Cells; Humans; Kupffer Cells; Liver Cirrhosis; Male; Mice, Inbred C57BL; Primary Cell Culture; Transforming Growth Factor beta; Vitamin D
PubMed: 31467426
DOI: 10.1038/s41374-019-0310-1 -
Neuroscience Bulletin Feb 2020Multiple sclerosis (MS) is a chronic and incurable autoimmune neurodegenerative disease of the central nervous system. Although the symptoms of MS can be managed by...
Multiple sclerosis (MS) is a chronic and incurable autoimmune neurodegenerative disease of the central nervous system. Although the symptoms of MS can be managed by vitamin D3 treatment alone, this condition cannot be completely eradicated. Thus, there might be unknown factors capable of regulating the vitamin D receptor (VDR). Genome-wide analysis showed that miRNAs were associated with VDRs. We sought to determine the role and mechanism of action of miRNA-125a-5p and VDRs in a model of MS, mice with experimental autoimmune encephalomyelitis (EAE), which was induced by myelin oligodendrocyte glycoprotein 35-55 peptides. EAE mice showed decreased mean body weight but increased mean clinical scores compared with vehicle or control mice. And inflammatory infiltration was found in the lumbosacral spinal cord of EAE mice. In addition, VDR expression was significantly lower while the expression of miR-125a-5p was markedly higher in the spinal ventral horn of EAE mice than in vehicle or control mice. Importantly, activation of VDRs by paricalcitol or inhibition of miR-125a-5p by its antagomir markedly decreased the mean clinical scores in EAE mice. Interestingly, VDR and miR-125a-5p were co-localized in the same neurons of the ventral horn. More importantly, inhibition of miR-125a-5p remarkably blocked the decrease of VDRs in EAE mice. These results support a critical role for miR-125a-5p in modulating VDR activity in EAE and suggest potential novel therapeutic interventions.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Female; Lumbosacral Region; Mice; Mice, Inbred C57BL; MicroRNAs; Multiple Sclerosis; Receptors, Calcitriol; Spinal Cord Ventral Horn
PubMed: 31428926
DOI: 10.1007/s12264-019-00418-0 -
Life Sciences Oct 2019Vitamin D and its receptor, vitamin D receptor (VDR), have renoprotection effect against diabetic nephropathy (DN). But the exact mechanism has not been fully...
AIMS
Vitamin D and its receptor, vitamin D receptor (VDR), have renoprotection effect against diabetic nephropathy (DN). But the exact mechanism has not been fully elucidated. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP) epoxygenase-derived metabolites of arachidonic acid, protecting against diabetes and DN. Herein, we hypothesized that activation of VDR attenuated high glucose-induced cellular injury in renal tubular epithelial cells partially through up-regulating CYP2J5 expression.
MAIN METHODS
Streptozotocin (STZ) was injected to induce diabetic in wild type and Vdr mice. The effects of VDR knockout and an activator of VDR, paricalcitol, on the renal injury were detected. In vitro, a murine kidney proximal tubule epithelial cell line BU.MPT induced by high glucose were treated with or without paricalcitol (30 mM) for 12 h or 24 h.
KEY FINDINGS
The expression of CYP2J5 was significantly decreased both in wild type and Vdr diabetic mice induced by STZ. The STZ-induced kidney architecture damage and apoptosis rate in Vdr mice were more severe. In vitro, high glucose treatment strongly reduced the CYP2J5 expression and the synthesis of 14,15-EET in BU.MPT cells. Supplement of 14,15-EET significantly reduced the lactate dehydrogenase (LDH) release induced by high glucose in BU.MPT cells. Furthermore, treatment with paricalcitol attenuated cellular injury and restored the expression of CYP2J5 reduced by high glucose in BU.MPT cells.
SIGNIFICANCE
We conclude that activation of VDR attenuates high glucose-induced cellular injury partially dependent on CYP2J5 in murine renal tubule epithelial cells and paricalcitol may represent a potential therapy for DN.
Topics: Animals; Cell Line; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Ergocalciferols; Gene Deletion; Gene Expression Regulation; Glucose; Kidney Tubules, Proximal; Male; Mice; Mice, Knockout; Receptors, Calcitriol
PubMed: 31415769
DOI: 10.1016/j.lfs.2019.116755 -
BMC Nephrology Aug 2019Microparticles (MPs) are biomarkers and mediators of disease through their expression of surface receptors, reflecting activation or stress in their parent cells.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Microparticles (MPs) are biomarkers and mediators of disease through their expression of surface receptors, reflecting activation or stress in their parent cells. Endothelial markers, ICAM-1 and VCAM-1, are implicated in atherosclerosis and associated with cardiovascular risk. Chronic kidney disease (CKD) patients have endothelial dysfunction and high levels of endothelial derived MPs. Vitamin D treatment has been reported to ameliorate endothelial function in CKD patients. We aimed to examine cell specific MP profiles and concentrations of MPs expressing the atherosclerotic markers ICAM-1 and VCAM-1 after treatment with paricalcitol in patients with CKD stage 3-4.
METHODS
Sub-study of the previously reported SOLID trial where 36 patients were randomly assigned to placebo, 1 or 2 μg paricalcitol, for 12 weeks. MPs were measured by flow cytometry after labelling with antibodies against endothelial (CD62E), platelet (CD62P, CD41, CD154) leukocyte (CD45) and vascular (CD54, CD106) markers.
RESULTS
Patients had a mean age of 65 years with a mean eGFR of 40 mL/min/1.73m. Concentrations of ICAM-1 positive MPs were significantly reduced by treatment (repeated measures ANOVA p = 0.04). Repeated measures MANOVA of concentrations of endothelial, platelet and leukocyte MPs showed sustained levels in the 2 μg treatment group (p = 0.85) but a decline in the 1 μg (p = 0.04) and placebo groups (p = 0.005).
CONCLUSIONS
Treatment with paricalcitol reduces concentrations of ICAM-1 positive MPs. This is accompanied by sustained concentrations of all cell specific MPs in the 2 μg group, and decreasing concentrations in the other groups, possibly due to a more healthy and reactive endothelium with paricalcitol treatment.
Topics: Aged; Aged, 80 and over; Cell-Derived Microparticles; Double-Blind Method; Ergocalciferols; Female; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; Receptors, Calcitriol; Renal Insufficiency, Chronic; Vascular Cell Adhesion Molecule-1
PubMed: 31370809
DOI: 10.1186/s12882-019-1445-4 -
Nefrologia 2020
Topics: Aged; Ankle; Bone Density Conservation Agents; Calciphylaxis; Calcium-Regulating Hormones and Agents; Cinacalcet; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Iron Overload; Leg Ulcer; Renal Insufficiency, Chronic
PubMed: 31255363
DOI: 10.1016/j.nefro.2019.03.015