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Iranian Journal of Medical Sciences Nov 2021Paricalcitol has been proposed for the treatment of secondary hyperparathyroidism in patients with renal failure and vitamin D deficiency (VDD); however, VDD is related...
BACKGROUND
Paricalcitol has been proposed for the treatment of secondary hyperparathyroidism in patients with renal failure and vitamin D deficiency (VDD); however, VDD is related to a range of clinical complaints. We aimed to investigate the effects of paricalcitol on body composition in VDD rats.
METHODS
Thirty adult male rats aged 10 weeks were randomly divided into three groups of 10, comprising control, VDD, and VDD plus paricalcitol (32 ng/rat intraperitoneal injection) (VDD+P), at the Animal Lab of the Endocrinology and Metabolism Research Center, Shiraz, Iran, in 2020. Body composition was assessed after three weeks via serum biochemical tests and dual-energy X-ray absorptiometry. Finally, the data were analyzed by using the paired-sample test, the one-way ANOVA, and the Tukey test.
RESULTS
Global lean mass and fat mass were lower in the VDD and VDD+P groups than in the controls (P<0.001). Global fat percentage was reduced significantly in the VDD+P group (P=0.029).
CONCLUSION
Paricalcitol reduced global fat mass and fat percentage in a rat model with VDD. Evaluation of insulin and adiponectin levels is suggested to clarify the physiology of paricalcitol in VDD states.
Topics: Animals; Body Composition; Ergocalciferols; Male; Rats; Vitamin D; Vitamin D Deficiency
PubMed: 34840387
DOI: 10.30476/ijms.2020.85368.1503 -
Journal of Cardiovascular Development... Oct 2021Vitamin D secosteroids are intranuclear regulators of cellular growth and suppress the renin-angiotensin system. The aim of this study was to test the hypothesis that...
Vitamin D secosteroids are intranuclear regulators of cellular growth and suppress the renin-angiotensin system. The aim of this study was to test the hypothesis that the vitamin D receptor agonist, paricalcitol (PC), either alone or with enalapril (E) (an angiotensin-converting enzyme inhibitor), reduces the progression of polycystic kidney disease. Preventative treatment of Lewis polycystic kidney (LPK) and Lewis control rats with PC (0.2 μg/kg i.p. 5 days/week) or vehicle from postnatal weeks 3 to 10 did not alter kidney enlargement. To evaluate the efficacy in established disease, LPK rats received either PC (0.8 μg/kg i.p; 3 days/week), vehicle, E (50 mg/L in water) or the combination of PC + E from weeks 10 to 20. In established disease, PC also did not alter the progression of kidney enlargement, kidney cyst growth or decline in renal function in LPK rats. Moreover, the higher dose of PC was associated with increased serum calcium and weight loss. However, in established disease, the combination of PC + E reduced systolic blood pressure and heart-body weight ratio compared to vehicle and E alone ( < 0.05). In conclusion, the combination of PC + E attenuated cardiovascular disease but caused hypercalcaemia and did not alter kidney cyst growth in LPK rats.
PubMed: 34821697
DOI: 10.3390/jcdd8110144 -
Annals of Palliative Medicine Oct 2021This study aimed to assimilate relevant domestic Chinese and international literature to describe and review the progress of research on the pharmacological actions of... (Review)
Review
OBJECTIVE
This study aimed to assimilate relevant domestic Chinese and international literature to describe and review the progress of research on the pharmacological actions of the multiple clinical effects and selectivity of the vitamin D (VD) analogue paricalcitol in multiple organs of the body.
BACKGROUND
Paricalcitol was the first VD analogue proven to be effective in the treatment of SHPT. With the discovery of vitamin D receptor (VDR) expression in different tissues and the disclosure of the corresponding physiological role, a large number of studies have shown that paricalcitol has a certain effect not only on SHPT, but also on other diseases such as kidney disease, cardiovascular disease, immune inflammatory response, and tumors.
METHODS
By referring to the relevant literature on vitamin D and its analogues at home and abroad from 1999 to 2020, the pharmacological characteristics of the pleiotropic and selective effects of paricalcitol were reviewed. PS software was used to map the molecular mechanism of paricalcitol in kidney, cardiovascular, bone metabolism, immune inflammation, and anti-tumor.
CONCLUSIONS
The novel VD analogue, paricalcitol, with its high selectivity for binding to VDR in vivo, maintains the efficacy of traditional VD drugs (targeting PTH and calcium and phosphorus metabolism) while providing additional benefits (reduction of urinary protein, reduction of inflammation, reduction of vascular calcification and renal fibrosis, and so on), thus expanding the application scope of future clinical practice.
Topics: Ergocalciferols; Humans; Vitamin D
PubMed: 34763476
DOI: 10.21037/apm-21-2249 -
Clinical Kidney Journal Nov 2021This study evaluates the effects of active (1α-hydroxylated) vitamin D (AVD) therapy on hypercalcaemia in patients with non-dialysis chronic kidney disease (ND-CKD) and...
Active vitamin D increases the risk of hypercalcaemia in non-dialysis chronic kidney disease patients with secondary hyperparathyroidism: a systematic review and meta-analysis.
BACKGROUND
This study evaluates the effects of active (1α-hydroxylated) vitamin D (AVD) therapy on hypercalcaemia in patients with non-dialysis chronic kidney disease (ND-CKD) and secondary hyperparathyroidism (SHPT).
METHODS
A systematic search of the PubMed, Embase and Cochrane Library databases (up to 14 May 2020) was performed to identify randomized, placebo-controlled trials of single-agent, oral AVD therapies in adults with ND-CKD and SHPT. Only studies with ≥30 participants per arm and ≥6 weeks in duration were eligible. The outcome of interest was the number of subjects with an episode of hypercalcaemia. A meta-analysis of eligible studies was conducted using Comprehensive Meta-Analysis software (version 3.0).
RESULTS
Six studies (five evaluating paricalcitol, one evaluating alfacalcidol) involving 799 patients were identified. Treatment durations ranged from 16 weeks to 2 years. The weekly doses of paricalcitol administered were 7 (three studies) and 14 µg (two studies); the weekly dose of alfacalcidol was 1.75-7.0 µg. Across all studies, rates of hypercalcaemia were 1.1-43.3% with AVD versus 0-3.4% with placebo. Meta-analysis of the six studies showed that AVD was associated with a 6.6-fold greater probability of hypercalcaemia versus placebo (odds ratio: 6.63, 95% confidence interval: 2.37, 18.55; P < 0.001). Two separate sensitivity analyses (one excluded a study identified as having a high risk of bias; the second excluded two studies that accounted for a large proportion of observed hypercalcaemia events) indicated the primary meta-analysis findings were robust.
CONCLUSIONS
Compared with placebo, AVD significantly increased the risk of hypercalcaemia among ND-CKD patients with SHPT.
PubMed: 34754440
DOI: 10.1093/ckj/sfab091 -
International Journal of Molecular... Oct 2021Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes , and , that affects the glomerular basement membrane of the... (Review)
Review
Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes , and , that affects the glomerular basement membrane of the kidney. It is a rare disease with an underestimated prevalence. Genetic analysis of population cohorts has revealed that it is the second most common inherited kidney disease after polycystic kidney disease. Renal involvement is the main manifestation, although it may have associated extrarenal manifestations such as hearing loss or ocular problems. The degree of expression of the disease changes according to the gene affected and other factors, known or yet to be known. The pathophysiology is not yet fully understood, although some receptors, pathways or molecules are known to be linked to the disease. There is also no specific treatment for Alport syndrome; the most commonly used are renin-angiotensin-aldosterone system inhibitors. In recent years, diagnosis has come a long way, thanks to advances in DNA sequencing technologies such as next-generation sequencing (NGS). Further research at the genetic and molecular levels in the future will complete the partial vision of the pathophysiological mechanism that we have, and will allow us to better understand what is happening and how to solve it.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen Type IV; Ergocalciferols; High-Throughput Nucleotide Sequencing; Humans; Integrins; Laminin; Nephritis, Hereditary; Polymorphism, Genetic
PubMed: 34681722
DOI: 10.3390/ijms222011063 -
Frontiers in Clinical Diabetes and... 2021Previous studies have shown that vitamin D analogs (such as paricalcitol) can reduce albuminuria in patients with diabetes mellitus and retard the progression of...
INTRODUCTION
Previous studies have shown that vitamin D analogs (such as paricalcitol) can reduce albuminuria in patients with diabetes mellitus and retard the progression of diabetic kidney disease (DKD). A recent systematic review reported significant improvement of renal function in patients with DKD who received vitamin D or its analogs. Study-driven data about their use in improving DKD outcomes have continued to accumulate over the years.
AIM
This paper aims to systematically review the contemporary evidence about the effectiveness of vitamin D analogs in retarding the onset or progression of DKD.
METHODS
With appropriate descriptors, two electronic databases (PubMed and Google Scholar) were searched for articles published between 2015 and 2021 in the English language. Primary studies that fulfilled the inclusion criteria were selected; their titles and abstracts were screened, and duplicates were removed. Relevant data were retrieved from the final selected studies using a preconceived data-extraction form.
RESULTS
A total of eight studies (three randomized-controlled trials, one prospective study, and four cross-sectional studies) were reviewed. A total of 6,243 participants were investigated in the eight studies and comprised young adults, middle-aged adults, and the elderly with a male-gender predominance. One randomized controlled trial reported that paricalcitol significantly improved renal function in type 1 diabetes patients with renal impairment when combined with renin-angiotensin-aldosterone system (RAAS) blockers. A strong correlation between vitamin D deficiency and DKD risk was noted in the majority of the cross-sectional studies. High doses of cholecalciferol (4,000 or 10,000 IU/day), given early in DKD, significantly reduced disease prevalence.
CONCLUSION
Paricalcitol may retard the onset or progression of DKD, especially if administered in combination with RAAS blockers. The association of vitamin D deficiency with DKD risk also supports this therapeutic effect. Future systematic reviews are still needed to strengthen the current evidence on therapeutic benefit of vitamin D or its analogs in DKD.
PubMed: 36994344
DOI: 10.3389/fcdhc.2021.763844 -
International Journal of Molecular... Sep 2021Recently, the role of kidney pericytes in kidney fibrosis has been investigated. This study aims to evaluate the effect of paricalcitol on hypoxia-induced and...
Recently, the role of kidney pericytes in kidney fibrosis has been investigated. This study aims to evaluate the effect of paricalcitol on hypoxia-induced and TGF-β1-induced injury in kidney pericytes. The primary cultured pericytes were pretreated with paricalcitol (20 ng/mL) for 90 min before inducing injury, and then they were exposed to TGF-β1 (5 ng/mL) or hypoxia (1% O and 5% CO). TGF-β1 increased α-SMA and other fibrosis markers but reduced PDGFRβ expression in pericytes, whereas paricalcitol reversed the changes. Paricalcitol inhibited the TGF-β1-induced cell migration of pericytes. Hypoxia increased TGF-β1, α-SMA and other fibrosis markers but reduced PDGFRβ expression in pericyte, whereas paricalcitol reversed them. Hypoxia activated the HIF-1α and downstream molecules including prolyl hydroxylase 3 and glucose transporter-1, whereas paricalcitol attenuated the activation of the HIF-1α-dependent molecules and TGF-β1/Smad signaling pathways in hypoxic pericytes. The gene silencing of HIF-1α vanished the hypoxia-induced TGF-β1, α-SMA upregulation, and PDGFRβ downregulation. The effect of paricalcitol on the HIF-1α-dependent changes of fibrosis markers was not significant after the gene silencing of HIF-1α. In addition, hypoxia aggravated the oxidative stress in pericytes, whereas paricalcitol reversed the oxidative stress by increasing the antioxidant enzymes in an HIF-1α-independent manner. In conclusion, paricalcitol improved the phenotype changes of pericyte to myofibroblast in TGF-β1-stimulated pericytes. In addition, paricalcitol improved the expression of fibrosis markers in hypoxia-exposed pericytes both in an HIF-1α-dependent and independent manner.
Topics: Animals; Cells, Cultured; Ergocalciferols; Fibrosis; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Mice; Myofibroblasts; Oxidative Stress; Pericytes; Phosphorylation; Protective Agents; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta1
PubMed: 34575914
DOI: 10.3390/ijms22189751 -
International Immunopharmacology Nov 2021Vitamin D receptor (VDR) and NLRP3 inflammasome play critical roles in lupus nephritis (LN) pathogenesis.
BACKGROUND
Vitamin D receptor (VDR) and NLRP3 inflammasome play critical roles in lupus nephritis (LN) pathogenesis.
AIM OF THE STUDY
This study explored the therapeutic effect of VDR agonist on LN and its molecular mechanism to inhibit NLRP3 signalling.
METHODS
C57BL/6 mice, lupus-prone MRL/lpr mice, and VDR agonist paricacitol-treated MRL/lpr mice (300 ng/kg/mouse per dose, 5 times/week for 8 weeks from 8 weeks old) were used to assess kidney histopathology and measure proteinuria, serum anti-ds-DNA antibody and expression of NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis. We used mouse renal tubular epithelial cells (mRTECs) to identify protein-protein interactions and examine the effects of paricalcitol.
RESULTS AND CONCLUSION
LN pathogenesis decreased after paricalcitol treatment. We observed a marked improvement in renal pathology and a time-dependent decrease urine protein and serum anti-dsDNA antibody levels. In 16-week-old MRL/lpr LN mice, the upregulated expression of NLRP3/caspase-1/IL-1β/IL-18 axis was significantly downregulated after paricalcitol treatment. Paricalcitol can reverse the apoptosis induced by anti-dsDNA antibody via the NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis in mRTECs. Furthermore, paricalcitol suppressed NF-κB nuclear translocation by competitively binding to importin-4. In summary, the VDR agonist can alleviate LN by modulating the NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis and suppressing the NF-κB nuclear translocation.
Topics: Animals; Apoptosis; Caspase 1; Caspases; Cell Culture Techniques; Ergocalciferols; Female; Interleukin-18; Interleukin-1beta; Karyopherins; Kidney; Lupus Nephritis; Mice; Mice, Inbred C57BL; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Receptors, Calcitriol; Signal Transduction
PubMed: 34536747
DOI: 10.1016/j.intimp.2021.108131 -
Nutrients Jul 2021In COVID-19 patients, low serum vitamin D (VD) levels have been associated with severe acute respiratory failure and poor prognosis. In regular hemodialysis (HD)... (Observational Study)
Observational Study
BACKGROUND
In COVID-19 patients, low serum vitamin D (VD) levels have been associated with severe acute respiratory failure and poor prognosis. In regular hemodialysis (HD) patients, there is VD deficiency and markedly reduced calcitriol levels, which may predispose them to worse outcomes of COVID-19 infection. Some hemodialysis patients receive treatment with drugs for secondary hyperparathyroidism, which have well known pleiotropic effects beyond mineral metabolism. The aim of this study was to evaluate the impact of VD status and the administration of active vitamin D medications, used to treat secondary hyperparathyroidism, on survival in a cohort of COVID-19 positive HD patients.
METHODS
A cross-sectional retrospective observational study was conducted from 12 March to 21 May 2020 in 288 HD patients with positive PCR for SARS-CoV2. Patients were from 52 different centers in Spain.
RESULTS
The percent of HD patients with COVID-19 was 6.1% (288 out of 4743). Mortality rate was 28.4% (81/285). Three patients were lost to follow-up. Serum 25(OH)D (calcidiol) level was 17.1 [10.6-27.5] ng/mL and was not significantly associated to mortality (OR 0.99 (0.97-1.01), = 0.4). Patients receiving active vitamin D medications (16/94 (17%) vs. 65/191(34%), = 0.003), including calcimimetics (4/49 (8.2%) vs. 77/236 (32.6%), = 0.001), paricalcitol or calcimimetics (19/117 (16.2%) vs. 62/168 (36.9%); < 0.001), and also those on both paricalcitol and calcimimetics, to treat secondary hyperparathyroidism (SHPTH) (1/26 (3.8%) vs. 80/259 (30.9%), < 0.001) showed a lower mortality rate than patients receiving no treatment with either drug. Multivariate Cox regression analysis confirmed this increased survival.
CONCLUSIONS
Our findings suggest that the use of paricalcitol, calcimimetics or the combination of both, seem to be associated with the improvement of survival in HD patients with COVID-19. No correlation was found between serum VD levels and prognosis or outcomes in HD patients with COVID-19. Prospective studies and clinical trials are needed to support these findings.
Topics: Aged; Aged, 80 and over; COVID-19; Calcifediol; Calcitriol; Calcium; Cross-Sectional Studies; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Renal Dialysis; Retrospective Studies; SARS-CoV-2; Survival Analysis; Vitamin D; Vitamin D Deficiency
PubMed: 34444716
DOI: 10.3390/nu13082559 -
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