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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 -
Nefrologia : Publicacion Oficial de La... 2016Secondary hyperparathyroidism (SHPT) is a common complication in patients with chronic kidney disease (CKD) that is characterised by elevated parathyroid hormone (PTH)... (Review)
Review
Secondary hyperparathyroidism (SHPT) is a common complication in patients with chronic kidney disease (CKD) that is characterised by elevated parathyroid hormone (PTH) levels and a series of bone-mineral metabolism anomalies. In patients with SHPT, treatment with paricalcitol, a selective vitamin D receptor activator, has been shown to reduce PTH levels with minimal serum calcium and phosphorus variations. The classic effect of paricalcitol is that of a mediator in mineral and bone homeostasis. However, recent studies have suggested that the benefits of treatment with paricalcitol go beyond PTH reduction and, for instance, it has a positive effect on cardiovascular disease and survival. The objective of this study is to review the most significant studies on the so-called pleiotropic effects of paricalcitol treatment in patients with CKD.
Topics: Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Minerals; Parathyroid Hormone; Phosphorus; Renal Insufficiency, Chronic
PubMed: 26705959
DOI: 10.1016/j.nefro.2015.11.003 -
Asian Journal of Andrology 2018Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers.... (Review)
Review
Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers. Epidemiologic data also indicate that vitamin D signaling may be important in the cause and prognosis of prostate and other cancers. These data indicate that perturbation of vitamin D signaling may be a target for the prevention and treatment of prostate cancer. Large studies of vitamin D supplementation will be required to determine whether these observations can be translated into prevention strategies. This paper reviews the available data in the use of vitamin D compounds in the treatment of prostate cancer. Clinical data are limited which support the use of vitamin D compounds in the management of men with prostate cancer. However, clinical trials guided by existing preclinical data are limited.
Topics: Antineoplastic Combined Chemotherapy Protocols; Calcifediol; Calcitriol; Clinical Trials as Topic; Ergocalciferols; Humans; Male; Prostatic Neoplasms; Signal Transduction; Vitamin D; Vitamin D Deficiency
PubMed: 29667615
DOI: 10.4103/aja.aja_14_18 -
Treatments in Endocrinology 2006black triangle An oral formulation of paricalcitol has been developed for the prevention and treatment of secondary hyperparathyroidism in patients with stage 3 or 4...
black triangle An oral formulation of paricalcitol has been developed for the prevention and treatment of secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease.black triangle Paricalcitol is a synthetic vitamin D analog that binds to the vitamin D receptor inducing suppression of parathyroid hormone (PTH) secretion.black triangle Oral paricalcitol was significantly more effective than placebo in treating secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease. In a pooled analysis of three well designed, 24-week trials, two consecutive reductions from baseline in intact PTH levels of >/=30% were achieved by significantly more paricalcitol than placebo recipients (91% vs 13%).black triangle In addition, mean levels of the biochemical bone markers serum bone-specific alkaline phosphatase, serum osteocalcin, and urinary pyridinoline were reduced from baseline to a significantly greater extent with paricalcitol than with placebo, indicating a reduction in bone turnover.black triangle Oral paricalcitol was well tolerated; there was no significant difference between paricalcitol and placebo recipients in the incidence of hypercalcemia, hyperphosphatemia, or elevated calcium-phosphorus product.
Topics: Calcium; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Parathyroid Hormone; Vitamin D
PubMed: 17002490
DOI: 10.2165/00024677-200605050-00005 -
Clinical Therapeutics Mar 1999Patients with end-stage renal disease commonly develop secondary hyperparathyroidism. Calcitriol may be administered to such patients to decrease the synthesis and... (Review)
Review
Patients with end-stage renal disease commonly develop secondary hyperparathyroidism. Calcitriol may be administered to such patients to decrease the synthesis and secretion of parathyroid hormone (PTH) and to help maintain calcium and phosphorus homeostasis. However, the doses of calcitriol required to suppress serum PTH concentrations can lead to hypercalcemia or hyperphosphatemia in many patients undergoing hemodialysis. Paricalcitol is a new vitamin D analogue that is safe and effective in suppressing elevated concentrations of PTH in patients with established hyperparathyroidism who are maintained on chronic hemodialysis. As with vitamin D, the biologic action of paricalcitol is mediated through activation of the vitamin D receptor (VDR). The VDR functions as a ligand-induced transcription factor regulating the rate of expression of genes that are involved in controlling not only calcium homeostasis and bone remodeling but also hormone secretion, inhibition of cell growth, and induction of cell differentiation. In vitro studies have shown that paricalcitol inhibits PTH secretion from bovine parathyroid cells in a dose-dependent manner. Studies in renally insufficient rats demonstrated that paricalcitol caused approximately 10 times less elevation of serum calcium concentrations than calcitriol. In clinical studies, paricalcitol effectively decreased PTH by about 60% over a 12-week period. Mean serum concentrations of calcium were significantly increased but remained within the normal range. There were occasional (5/414 determinations) transient elevations in serum calcium above the upper limit of normal in some (5/401) patients. Serum phosphorus values did not change significantly compared with baseline, although they tended to be slightly higher in the paricalcitol-treated group than in the group receiving placebo. Elevations of the calcium-times-phosphorus product were relatively few but occurred more often in the paricalcitol than in the placebo group. The terminal half-life of paricalcitol was 5 to 7 hours in healthy subjects; in patients undergoing hemodialysis, it was 14 hours. Adverse events associated with paricalcitol use included, among others, chills, feeling unwell, fever, sepsis, palpitations, dry mouth, gastrointestinal bleeding, nausea, vomiting, edema, light-headedness, and pneumonia. Paricalcitol should be considered as an alternative to calcitriol in the treatment of patients who are undergoing maintenance hemodialysis for end-stage renal disease, as it has a decreased potential to induce hypercalcemia and hyperphosphatemia. Additional studies are required to determine the long-term effects of therapy.
Topics: Animals; Clinical Trials, Phase III as Topic; Ergocalciferols; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Renal Dialysis
PubMed: 10321413
DOI: 10.1016/S0149-2918(00)88299-5 -
Oxidative Medicine and Cellular... 2022Transition from cardiac hypertrophy to failure involves adverse metabolic reprogramming involving mitochondrial dysfunction. We have earlier shown that vitamin D...
OBJECTIVES
Transition from cardiac hypertrophy to failure involves adverse metabolic reprogramming involving mitochondrial dysfunction. We have earlier shown that vitamin D deficiency induces heart failure, at least in part, through insulin resistance. However, whether activation of vitamin D receptor (VDR) can attenuate heart failure and underlying metabolic phenotype requires investigation. Thus, we aimed to assess the cardioprotective potential of paricalcitol, a vitamin D receptor-activator, against cardiac hypertrophy and failure in high-fat high-fructose-fed rats.
METHODS
Male Sprague Dawley rats were fed control (Con) or high-fat high-fructose (HFHFrD) diet for 20 weeks. After 12 weeks, rats from HFHFrD group were divided into the following: HFHFrD, HFHFrD+P (paricalcitol 0.08 g/kg/day) and HFHFrD+E (enalapril maleate 10 mg/kg/day). Intraperitoneal glucose tolerance test, blood pressure measurement, and 2D echocardiography were performed. Cardiac fibrosis was assessed by Masson's trichrome staining of paraffin-embedded heart sections. Mitochondrial DNA and proteins, and citrate synthase activity were measured in rat hearts. VDR was silenced in H9c2 cardiomyoblasts, and immunoblotting was performed.
RESULTS
Paricalcitol improved glucose tolerance, serum lipid profile, and blood pressure in high-fat high-fructose-fed rats. Paricalcitol reduced cardiac wall thickness and increased ejection fraction in high-fat high-fructose-fed rats but had no effect on perivascular fibrosis. PGC1- was upregulated in the HFHFrD+P group compared to the HFHFrD group, but there was no significant difference in mitochondrial content. Citrate synthase activity was significantly higher in the HFHFrD+P group compared to the HFHFrD group. Rat hearts of the HFHFrD+P group had significantly higher expression of mitofusins. H9c2 cells with VDR knockdown showed significantly lower expression of Mfn2. Improvement in the HFHFrD+P group was comparable with that in the HFHFrD+E group.
CONCLUSIONS
Paricalcitol reverses cardiac dysfunction in rats with metabolic syndrome by enhancing mitochondrial fusion. We demonstrate repurposing potential of the drug currently used in end-stage kidney disease.
Topics: Animals; Cardiomegaly; Citrate (si)-Synthase; Ergocalciferols; Fructose; Heart Failure; Male; Metabolic Syndrome; Mitochondrial Dynamics; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol
PubMed: 35726330
DOI: 10.1155/2022/5554290 -
Treatments in Endocrinology 2005Paricalcitol (Zemplar) is a synthetic vitamin D2 analog that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is... (Review)
Review
Paricalcitol (Zemplar) is a synthetic vitamin D2 analog that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is approved in the US and in most European nations for intravenous use in the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure in adult, and in the US pediatric, patients. Paricalcitol effectively reduced elevated serum PTH levels and was generally well tolerated in children and adults with secondary hyperparathyroidism associated with chronic renal failure. In well designed clinical trials, paricalcitol was as effective as calcitriol and as well tolerated in terms of the incidence of prolonged hypercalcemia and/or elevated calcium-phosphorus product (Ca x P). Thus, paricalcitol is a useful option for the management of secondary hyperparathyroidism in adults and children with chronic renal failure.
Topics: Adult; Child; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Parathyroid Hormone
PubMed: 15898824
DOI: 10.2165/00024677-200504030-00007 -
Current Vascular Pharmacology Mar 2014The activation of vitamin D receptors (VDR) - (including activation by 25-hydroxyvitamin D) - seems to have not only mineral-metabolism beneficial effects but also... (Review)
Review
The activation of vitamin D receptors (VDR) - (including activation by 25-hydroxyvitamin D) - seems to have not only mineral-metabolism beneficial effects but also important extra-skeletal actions. Paricalcitol is a synthetic vitamin D2 agonist of the VDR approved for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD). As a result of its selectivity, paricalcitol provides a wider therapeutic window for PTH suppression, minimizing deleterious effects of high serum calcium and/or phosphate concentrations. Paricalcitol also shares, and sometimes improves pleiotropic vitamin-D related systemic effects. For instance, paricalcitol has been repeatedly shown to decrease calcium and phosphate deposition in vessels and to decrease the expression of osteogenic factors preventing the active transformation of smooth muscle vascular cells into osteoblast-like cells in experimental models. In patients, paricalcitol has been associated with improved survival of dialysis patients and it may improve residual albuminuria in diabetic patients. Consequently, paricalcitol may enhance the standard of care in these high-risk patients. Although it seems reasonable to use these potential advantages to guide the individual and integral management of the complex CKD-mineral and bone disorder, it is necessary to recognize that many of these observations have not been proven nor confirmed in prospective clinical trials.
Topics: Animals; Calcium; Ergocalciferols; Heart; Humans; Hyperparathyroidism, Secondary; Kidney; Phosphates; Receptors, Calcitriol; Renal Insufficiency, Chronic
PubMed: 23713879
DOI: 10.2174/15701611113119990028 -
Drugs 2005Paricalcitol (Zemplar) is a synthetic vitamin D(2) analogue that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is... (Review)
Review
Paricalcitol (Zemplar) is a synthetic vitamin D(2) analogue that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is approved in the US and in most European nations for intravenous use in the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure in adult, and in the US paediatric, patients. Paricalcitol effectively reduced elevated serum PTH levels and was generally well tolerated in children and adults with secondary hyperparathyroidism associated with chronic renal failure. In well designed clinical trials, paricalcitol was as effective as calcitriol and as well tolerated in terms of the incidence of prolonged hypercalcaemia and/or elevated calcium-phosphorus product (Ca x P). Thus, paricalcitol is a useful option for the management of secondary hyperparathyroidism in adults and children with chronic renal failure.
Topics: Clinical Trials as Topic; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic
PubMed: 15733015
DOI: 10.2165/00003495-200565040-00008 -
Expert Opinion on Pharmacotherapy Apr 2006Secondary hyperparathyroidism is a common complication of patients with chronic kidney disease. Treatment with calcitriol, the active form of vitamin D, reduces... (Comparative Study)
Comparative Study Review
Secondary hyperparathyroidism is a common complication of patients with chronic kidney disease. Treatment with calcitriol, the active form of vitamin D, reduces parathyroid hormone levels, but may result in elevations in serum calcium and phosphorus. New vitamin D analogues have been developed to reduce parathyroid hormone secretion without concomitant hypercalcaemia and hyperphosphataemia. Recent data from studies with paricalcitol capsules, the oral formulation of 19-nor-1,25(OH)2D2, show a significant reduction in parathyroid hormone levels with no change in calcium and phosphorus levels when compared with placebo. Paricalcitol also compares favourably to other oral vitamin D analogues, effectively decreasing parathyroid secretion with less hypercalcaemia and hypercalciuria than other agents.
Topics: Capsules; Chronic Disease; Drug Administration Schedule; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Parathyroid Hormone; Randomized Controlled Trials as Topic; Vitamin D; Vitamins
PubMed: 16553577
DOI: 10.1517/14656566.7.5.617