-
Autophagy Apr 2022Diabetic nephropathy (DN) has become a major cause of end-stage renal disease, and autophagy disorder is implicated in the pathogenesis of DN. Our previous studies found...
Diabetic nephropathy (DN) has become a major cause of end-stage renal disease, and autophagy disorder is implicated in the pathogenesis of DN. Our previous studies found that vitamin D (VD) and VDR (vitamin D receptor) played a renoprotective role by inhibiting inflammation and fibrosis. However, whether VD-VDR regulates autophagy disorders in DN remains unclear. In this study, we established a streptozotocin (STZ)-induced diabetic model in knockout (-KO) mice and VDR specifically overexpressed in renal proximal tubular epithelial cells (-OE) mice. Our results showed that paricalcitol (an activated vitamin D analog) or -OE could alleviate STZ-induced ALB (albumin) excretion, renal tubule injury and inflammation, while these were worsened in -KO mice. Defective autophagy was observed in the kidneys of STZ mice, which was more pronounced in -KO mice and could be partially restored by paricalcitol or -OE. In high glucose-induced HK-2 cells, defective autophagy and decreased PRKAA1/AMPK phosphorylation was observed, which could be partially restored by paricalcitol in a VDR-dependent manner. AMPK inhibitor abolished paricalcitol-induced autophagy activation, and AMPK activator restored the defective autophagy in high glucose-induced HK-2 cells. Furthermore, paricalcitol-mediated AMPK activation was abrogated by CAMKK2/CaMKKβ inhibition, but not by knockout. Meanwhile, paricalcitol rescued the decreased Ca concentration induced by high glucose. In conclusion, VD-VDR can restore defective autophagy in the kidney of STZ-induced diabetic mice, which could be attributed to the activation of the Ca-CAMKK2-AMPK pathway in renal tubular epithelial cells. ACTB/β-actin: actin beta;AGE: advanced glycation end-products;AMPK: AMP-activated protein kinase;CAMKK2/CaMKKβ: calcium-calmodulin dependent protein kinase kinase 2;CQ: chloroquine;DN: diabetic nephropathy;HG: high levels of glucose;KO: knockout;LG: low levels of glucose;MAP1LC3/LC3: microtubule associated protein 1 light chain 3;NOD2: nucleotide binding oligomerization domain containing 2;OE: overexpression;PAS: periodic acid Schiff; Pari: paricalcitol;PTECs: proximal renal tubule epithelial cells;RT: room temperature;SQSTM1/p62: sequestosome 1;STK11/LKB1: serine/threonine kinase 11;STZ: streptozotocin;TEM: transmission electron microscopy;VD: vitamin D;VDR: vitamin D receptor;WT: wild-type.
Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Epithelial Cells; Female; Glucose; Humans; Inflammation; Male; Mice; Mice, Knockout; Receptors, Calcitriol; Streptozocin; Vitamin D; Vitamins
PubMed: 34432556
DOI: 10.1080/15548627.2021.1962681 -
Scientific Reports Aug 2021Idiopathic pulmonary fibrosis (IPF) is a severe disorder leading to progressive and irreversible loss of pulmonary function. In this study we investigated the...
Idiopathic pulmonary fibrosis (IPF) is a severe disorder leading to progressive and irreversible loss of pulmonary function. In this study we investigated the anti-fibrotic effect of vitamin D using a mouse model of IPF. Lung fibrosis was induced with bleomycin in vitamin D-sufficient and vitamin D-deficient C57BL/6 mice. We found that treatment with active vitamin D analog paricalcitol prevented mouse body weight loss and alleviated lung fibrosis, whereas vitamin D deficiency severely aggravated lung injury. At the molecular level, paricalcitol treatment suppressed the induction of fibrotic inducer TGF-β and extracellular matrix proteins α-SMA, collagen type I and fibronectin in the lung, whereas vitamin D deficiency exacerbated the induction of these proteins. Interestingly, bleomycin treatment activated the local renin-angiotensin system (RAS) in the lung, manifested by the induction of renin, angiotensinogen, angiotensin II and angiotensin receptor type 1 (AT1R). Paricalcitol treatment suppressed the induction of these RAS components, whereas vitamin D deficiency enhanced the activation of the lung RAS. We also showed that treatment of bleomycin-induced vitamin D-deficient mice with AT1R antagonist losartan relieved weight loss, substantially ameliorated lung fibrosis and markedly blocked TGF-β induction in the lung. Moreover, we demonstrated that in lung fibroblast cultures, TGF-β and angiotensin II synergistically induced TGF-β, AT1R, α-SMA, collagen type I and fibronectin, whereas 1,25-dihydroxyvitamin D markedly suppressed the induction of these fibrotic markers. Collectively, these observations strongly suggest that vitamin D mitigates lung fibrosis by blocking the activation of the lung RAS in this mouse model of IPF.
Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Bleomycin; Disease Models, Animal; Ergocalciferols; Losartan; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Pulmonary Fibrosis; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Transforming Growth Factor beta; Vitamin D
PubMed: 34400742
DOI: 10.1038/s41598-021-96152-7 -
Frontiers in Public Health 2021Chronic Kidney Disease (CKD) is a global chronic disease with increasing prevalence in recent years, particularly CKD accompanied by Secondary Hyperparathyroidism...
Chronic Kidney Disease (CKD) is a global chronic disease with increasing prevalence in recent years, particularly CKD accompanied by Secondary Hyperparathyroidism (SHPT) leads to reduced quality of life, increased mortality, a considerable economic burden for patients and society. The aim of this study was to investigate the cost-effectiveness analysis of paricalcitol vs. calcitriol + cinacalcet for CKD patients with SHPT in China in 2020. A Markov model was conducted employing data derived from published literature, clinical trials, official sources, and tertiary public hospital data in China, based on a 10-year horizon from the perspective of the healthcare system. Calcitriol + Cinacalcet was used as the reference group. CKD stage 5 (CKD-5) dialysis patients suffering from SHPT were included in the study. Effectiveness was measured in quality-adjusted life years (QALYs). The discount rate (5%) was applied to costs and effectiveness. Sensitivity analysis was performed to confirm the robustness of the findings. The base case analysis demonstrated that Patients treated with paricalcitol could gain an increase in utility (0.183 QALYs) and require fewer expenditures (6925.612 yuan). One-way sensitivity analysis was performed to showed that impact factors were the price of cinacalcet, the hospitalization costs of patients with paricalcitol and calcitriol, the costs and utilities of hemodialysis and the costs of calcitriol, the costs of paricalcitol regardless of period. Probabilistic simulation analysis displayed when willingness-to-pay was ¥217113, the probability that Paricalcitol was dominant is 96.20%. The results showed that paricalcitol administrated to treat patients diagnosed with Secondary hyperparathyroidism in Chronic Kidney Disease, compared to calcitriol and cinacalcet, might be dominant in China.
Topics: Calcitriol; Cinacalcet; Cost-Benefit Analysis; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 34368073
DOI: 10.3389/fpubh.2021.712027 -
Calcified Tissue International Aug 2021A large proportion of patients with chronic kidney disease (CKD) are vitamin D deficient (plasma 25-hydroxyvitamin D (25(OH)D) < 25 or 30 nmol/L per UK and US... (Meta-Analysis)
Meta-Analysis
Vitamin D Supplementation for Patients with Chronic Kidney Disease: A Systematic Review and Meta-analyses of Trials Investigating the Response to Supplementation and an Overview of Guidelines.
A large proportion of patients with chronic kidney disease (CKD) are vitamin D deficient (plasma 25-hydroxyvitamin D (25(OH)D) < 25 or 30 nmol/L per UK and US population guidelines) and this contributes to the development of CKD-mineral bone disease (CKD-MBD). Gaps in the evidence-base for the management of vitamin D status in relation to CKD-MBD are hindering the formulation of comprehensive guidelines. We conducted a systemic review of 22 RCTs with different forms of vitamin D or analogues with CKD-MBD related outcomes and meta-analyses for parathyroid hormone (PTH). We provide a comprehensive overview of current guidelines for the management of vitamin D status for pre-dialysis CKD patients. Vitamin D supplementation had an inconsistent effect on PTH concentrations and meta-analysis showed non- significant reduction (P = 0.08) whereas calcifediol, calcitriol and paricalcitol consistently reduced PTH. An increase in Fibroblast Growth Factor 23 (FGF23) with analogue administration was found in all 3 studies reporting FGF23, but was unaltered in 4 studies with vitamin D or calcifediol. Few RCTS reported markers of bone metabolism and variations in the range of markers prevented direct comparisons. Guidelines for CKD stages G1-G3a follow general population recommendations. For the correction of deficiency general or CKD-specific patient guidelines provide recommendations. Calcitriol or analogues administration is restricted to stages G3b-G5 and depends on patient characteristics. In conclusion, the effect of vitamin D supplementation in CKD patients was inconsistent between studies. Calcifediol and analogues consistently suppressed PTH, but the increase in FGF23 with calcitriol analogues warrants caution.
Topics: Dietary Supplements; Fibroblast Growth Factor-23; Humans; Parathyroid Hormone; Renal Insufficiency, Chronic; Vitamin D; Vitamin D Deficiency
PubMed: 33895867
DOI: 10.1007/s00223-021-00844-1 -
Frontiers in Endocrinology 2021Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin... (Review)
Review
Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin D with particular reference to COVID-19 and pancreatic cancer. Utility as a therapeutic agent is limited by hypercalcemic effects and attempts to circumvent this problem have used vitamin D superagonists, with increased efficacy and reduced calcemic effect. A further caveat is that vitamin D mediates multiple diverse effects. Some of these (anti-fibrosis) are likely beneficial in patients with COVID-19 and pancreatic cancer, whereas others (reduced immunity), may be beneficial through attenuation of the cytokine storm in patients with advanced COVID-19, but detrimental in pancreatic cancer. Vitamin D superagonists represent an untapped resource for development of effective therapeutic agents. However, to be successful this approach will require agonists with high cell-tissue specificity.
Topics: Carcinoma, Pancreatic Ductal; Cytokine Release Syndrome; Humans; Pancreatic Neoplasms; Vitamin D; Vitamins; COVID-19 Drug Treatment
PubMed: 33868174
DOI: 10.3389/fendo.2021.644298 -
International Journal of Molecular... Feb 2021Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). MS and its animal model called experimental autoimmune encephalomyelitis... (Comparative Study)
Comparative Study
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). MS and its animal model called experimental autoimmune encephalomyelitis (EAE) immunopathogenesis involve a plethora of immune cells whose activation releases a variety of proinflammatory mediators and free radicals. Vitamin D3 (VitD) is endowed with immunomodulatory and antioxidant properties that we demonstrated to control EAE development. However, this protective effect triggered hypercalcemia. As such, we compared the therapeutic potential of VitD and paricalcitol (Pari), which is a non-hypercalcemic vitamin D analog, to control EAE. From the seventh day on after EAE induction, mice were injected with VitD or Pari every other day. VitD, but not Pari, displayed downmodulatory ability being able to reduce the recruitment of inflammatory cells, the mRNA expression of inflammatory parameters, and demyelination at the CNS. Lower production of proinflammatory cytokines by lymph node-derived cells and IL-17 by gut explants, and reduced intestinal inflammation were detected in the EAE/VitD group compared to the EAE untreated or Pari groups. Dendritic cells (DCs) differentiated in the presence of VitD developed a more tolerogenic phenotype than in the presence of Pari. These findings suggest that VitD, but not Pari, has the potential to be used as a preventive therapy to control MS severity.
Topics: Animals; Antioxidants; Bone Marrow Cells; Cholecalciferol; Cytokines; Dendritic Cells; Encephalomyelitis, Autoimmune, Experimental; Ergocalciferols; Female; Immunologic Factors; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Post-Exposure Prophylaxis; Severity of Illness Index; Signal Transduction; Treatment Outcome
PubMed: 33671896
DOI: 10.3390/ijms22041914 -
Medicina (Kaunas, Lithuania) Feb 2021Vitamin D presents a plethora of different functions that go beyond its role in skeletal homeostasis. It is an efficient endocrine regulator of the... (Review)
Review
Vitamin D presents a plethora of different functions that go beyond its role in skeletal homeostasis. It is an efficient endocrine regulator of the Renin-Angiotensin-Aldosterone System (RAAS) and erythropoiesis, exerts immunomodulatory effects, reduces the cardiovascular events and all-cause mortality. In Chronic Kidney Disease (CKD) patients, Vitamin D function is impaired; the renal hydrolyzation of its inactive form by the action of 1α-hydroxylase declines at the same pace of reduced nephron mass. Moreover, Vitamin D major carrier, the D-binding protein (DBP), is less represented due to Nephrotic Syndrome (NS), proteinuria, and the alteration of the cubilin-megalin-amnionless receptor complex in the renal proximal tubule. In Glomerulonephritis (GN), Vitamin D supplementation demonstrated to significantly reduce proteinuria and to slow kidney disease progression. It also has potent antiproliferative and immunomodulating functions, contributing to the inhibitions of kidney inflammation. Vitamin D preserves the structural integrity of the slit diaphragm guaranteeing protective effects on podocytes. Activated Vitamin D has been demonstrated to potentiate the antiproteinuric effect of RAAS inhibitors in IgA nephropathy and Lupus Nephritis, enforcing its role in the treatment of glomerulonephritis: calcitriol treatment, through Vitamin D receptor (VDR) action, can regulate the heparanase promoter activity and modulate the urokinase receptor (uPAR), guaranteeing podocyte preservation. It also controls the podocyte distribution by modulating mRNA synthesis and protein expression of nephrin and podocin. Maxalcalcitol is another promising alternative: it has about 1/600 affinity to vitamin D binding protein (DBP), compared to Calcitriol, overcoming the risk of hypercalcemia, hyperphosphatemia and calcifications, and it circulates principally in unbound form with easier availability for target tissues. Doxercalciferol, as well as paricalcitol, showed a lower incidence of hypercalcemia and hypercalciuria than Calcitriol. Paricalcitol demonstrated a significant role in suppressing RAAS genes expression: it significantly decreases angiotensinogen, renin, renin receptors, and vascular endothelial growth factor (VEGF) mRNA levels, thus reducing proteinuria and renal damage. The purpose of this article is to establish the Vitamin D role on immunomodulation, inflammatory and autoimmune processes in GN.
Topics: Glomerulonephritis; Humans; Podocytes; Receptors, Calcitriol; Vascular Endothelial Growth Factor A; Vitamin D
PubMed: 33671780
DOI: 10.3390/medicina57020186 -
Nutrition, Metabolism, and... Jan 2021Cardiovascular disease is the main cause of death worldwide, but the collective efforts to prevent this pathological condition are directed exclusively to individuals at...
BACKGROUND AND AIMS
Cardiovascular disease is the main cause of death worldwide, but the collective efforts to prevent this pathological condition are directed exclusively to individuals at higher risk due to hypercholesterolemia, hypertension, obesity, diabetes. Recently, vitamin D deficiency was identified as a risk factor for cardiovascular disease in healthy people, as it predisposes to different vascular dysfunctions that can result in plaque development and fragility. In this scenario, the fundamental aim of the study was to reproduce a disease model inducing vitamin D deficiency and atheromatosis in ApoE mice and then to evaluate the impact of this vitamin D status on the onset/progression of atheromatosis, focusing on plaque formation and instability.
METHODS AND RESULTS
In our murine disease model, vitamin D deficiency was achieved by 3 weeks of vitamin D deficient diet along with intraperitoneal paricalcitol injections, while atheromatosis by western-type diet administration. Under these experimental conditions, vitamin D deficient mice developed more unstable atheromatous plaques with reduced or absent fibrotic cap. Since calcium and phosphorus metabolism and also cholesterol and triglycerides systemic concentration were not affected by vitamin D level, our results highlighted the role of vitamin D deficiency in the formation/instability of atheromatous plaque and, although further studies are needed, suggested a possible intervention with vitamin D to prevent or delay the atheromatous disease.
CONCLUSIONS
The data obtained open the question about the potential role of the vitamins in the pharmacological treatments of cardiovascular disorders as coadjutant of the primary drugs used for these pathologies.
Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Biomarkers; Diet, High-Fat; Disease Models, Animal; Fibrosis; Lipids; Mice, Knockout, ApoE; Plaque, Atherosclerotic; Rupture, Spontaneous; Vitamin D; Vitamin D Deficiency; Mice
PubMed: 33500110
DOI: 10.1016/j.numecd.2020.08.031 -
Biochimica Et Biophysica Acta.... Mar 2021Although vitamin D (VD) is chemoprotective and enhances 5-fluorouracil (5-FU) cytotoxicity against colorectal cancer (CRC), little is known about its potential calcium...
Chemopreventive effects of vitamin D and its analogue, paricalcitol, in combination with 5-fluorouracil against colorectal cancer: The role of calcium signalling molecules.
BACKGROUND
Although vitamin D (VD) is chemoprotective and enhances 5-fluorouracil (5-FU) cytotoxicity against colorectal cancer (CRC), little is known about its potential calcium (Ca)-mediated anti-tumorigenic actions. Therefore, this study compared between VD and its non-calcaemic analogue, Paricalcitol (Pcal), ± 5-FU in relation to chemoprevention and Ca-mediated apoptosis in vivo and in vitro.
METHODS
Seventy male mice were distributed to: negative controls, positive controls (PC), VD, Pcal, 5-FU, VD + 5-FU and Pcal+5-FU groups. All groups, except negative, received two consecutive azoxymethane (AOM)-injections (10 mg/Kg/week) for CRC induction. VD (1000 IU/kg; three times/week) and Pcal (1.25 μg/kg; three times/week) injections started week-16 post-AOM and for 10 weeks. Three successive 5-FU cycles began at week-21 (50 mg/Kg/week). Similar protocols with VD, Pcal and/or 5-FU were applied in the HT29 colon cancer cells.
RESULTS
The PC group had abundant malignant tumours, markedly elevated proliferation markers (survivin/CCND1) and declines in cyclin-dependent kinase-inhibitor-1A, pro-apoptotic molecules (p53/BAX/cytochrome_C/caspase-3), tissue Ca concentrations and Ca-dependent proteins (CaSR/CAM/CAMKIIA). All monotherapies equally reduced tumour numbers and proliferation markers whilst promoting the anti-tumorigenic molecules. VD and/or 5-FU, but not Pcal monotherapy, enhanced Ca levels and Ca-related molecules (CaSR/CAM/CAMKIIA/BAX/cytochrome_C) in vivo and in vitro. However, VD + 5-FU co-therapy showed the lowest tumour numbers, the highest cell numbers in sub-G1 phase of cell cycle, alongside the most effective modulations of oncogenes, tumour suppressors and Ca-related molecules at the gene and protein levels in vivo and in vitro.
CONCLUSIONS
VD was superior than Paricalcitol in potentiating 5-FU cytotoxicity, possibly by upregulating several Ca-related molecules involved in tumour suppression.
Topics: Animals; Anticarcinogenic Agents; Calcium; Calcium Signaling; Cell Cycle Checkpoints; Cholecalciferol; Colorectal Neoplasms; Disease Progression; Ergocalciferols; Fluorouracil; HT29 Cells; Humans; Male; Mice; Mice, Inbred BALB C
PubMed: 33338596
DOI: 10.1016/j.bbadis.2020.166040 -
PloS One 2020Following a successful renal transplantation circulating markers of inflammation may remain elevated, and systemic inflammation is associated with worse clinical outcome...
Following a successful renal transplantation circulating markers of inflammation may remain elevated, and systemic inflammation is associated with worse clinical outcome in renal transplant recipients (RTRs). Vitamin D-receptor (VDR) activation is postulated to modulate inflammation and endothelial function. We aimed to explore if a synthetic vitamin D, paricalcitol, could influence systemic inflammation and immune activation in RTRs. Newly transplanted RTRs were included in an open-label randomized controlled trial on the effect of paricalcitol on top of standard care over the first post-transplant year. Fourteen pre-defined circulating biomarkers reflecting leukocyte activation, endothelial activation, fibrosis and general inflammatory burden were analyzed in 74 RTRs at 8 weeks (baseline) and 1 year post-engraftment. Mean changes in plasma biomarker concentrations were compared by t-test. The expression of genes coding for the same biomarkers were investigated in 1-year surveillance graft biopsies (n = 60). In patients treated with paricalcitol circulating osteoprotegerin levels increased by 0.19 ng/ml, compared with a 0.05 ng/ml increase in controls (p = 0.030). In graft tissue, a 21% higher median gene expression level of TNFRSF11B coding for osteoprotegerin was found in paricalcitol-treated patients compared with controls (p = 0.026). Paricalcitol treatment did not significantly affect the blood- or tissue levels of any other investigated inflammatory marker. In RTRs, paricalcitol treatment might increase both circulating and tissue levels of osteoprotegerin, a modulator of calcification, but potential anti-inflammatory treatment effects in RTRs are likely very modest. [NCT01694160 (2012/107D)]; [www.clinicaltrials.gov].
Topics: Biomarkers; Ergocalciferols; Female; Gene Expression Regulation; Humans; Inflammation; Kidney Transplantation; Leukocytes; Male; Middle Aged
PubMed: 33326471
DOI: 10.1371/journal.pone.0243759