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Paricalcitol Attenuates Contrast-Induced Acute Kidney Injury by Regulating Mitophagy and Senescence.Oxidative Medicine and Cellular... 2020Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital-acquired renal failure, with an incidence of 11%. However, the disease mechanism...
Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital-acquired renal failure, with an incidence of 11%. However, the disease mechanism remains unclear, and no effective treatment is available. Paricalcitol has been reported to be effective in animal models of kidney injury. We hypothesized that paricalcitol could play a renoprotective role against CI-AKI. Rats were divided into control, paricalcitol, contrast, and paricalcitol-plus-contrast groups. We used a previously published protocol to produce CI-AKI. Paricalcitol (0.3 g/kg) was administered intraperitoneally before 24 h and 30 min before indomethacin. We used HK-2 cells to evaluate the effects of paricalcitol on mitophagy and senescence. Ioversol triggered renal dysfunction, increasing blood urea nitrogen and serum creatinine. Significant tubular damage, increased 8-OHdG expression, and apoptosis were apparent. Ioversol injection induced high expression levels of the mitophagy markers Pink1, Parkin, and LC3 and the senescence markers -galactosidase and p16INK4A. Paricalcitol pretreatment prevented renal dysfunction and reduced tissue damage by reducing both mitophagy and senescence. Cellular morphological changes were found, and expression of LC3B and HMGB1 was increased by ioversol in HK-2 cells. Paricalcitol countered these effects. This study showed that mitochondria might drive injury phenotypes in CI-AKI, and that paricalcitol protects against CI-AKI by decreasing mitochondrial damage.
Topics: Acute Kidney Injury; Animals; Contrast Media; Epithelial Cells; Ergocalciferols; Kidney; Kidney Tubules; Male; Mitochondria; Mitophagy; Rats; Ubiquitin-Protein Ligases
PubMed: 33299530
DOI: 10.1155/2020/7627934 -
Journal of Diabetes Research 2020Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement...
BACKGROUND
Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy worldwide. Vitamin D levels in DN patients are very low due to the decrease in the synthesis and activity of 1- hydroxylase in the proximal tubule cells and decrease in the vitamin D receptor abundance. To date, few studies have shown the antioxidant effects of 1,25-dihydroxyvitamin D [1,25(OH)D] on hyperglycemia-induced renal injury. The selective activator of the vitamin D receptor, paricalcitol, reduces proteinuria and slows the progression of kidney injury. The precise mechanism through which vitamin D affects diabetic status and provides kidney protection remains to be determined.
METHODS
Diabetes mellitus (DM) was induced in 94 8-week-old DBA/2J mice by intraperitoneal injection of streptozotocin (STZ). DM mice were randomly divided into receiving vehicle or treatment with paricalcitol, the active vitamin D analog, 1 week after DM induction or paricalcitol treatment 3 weeks after DM induction. An additional control group of healthy wild-type mice was not treated. Urine albumin, blood urea nitrogen, and creatinine levels were measured before and at the end of the paricalcitol treatment. Periodic acid-Schiff, immunohistochemistry staining, and western blot of the renal tissues of vitamin D receptor, villin, nephrin, and podocin expressions, were analyzed.
RESULTS
Paricalcitol treatment restored villin, nephrin, and podocin protein levels that were downregulated upon DM induction, and reduced fibronectin protein level. Vitamin D receptor activation by paricalcitol may reduce proteinuria of DN in mice and alleviate high-glucose-induced injury of kidney podocytes by regulating the key molecules such nephrin-podocin.
CONCLUSIONS
Paricalcitol treatment was associated with improved structural changes in type 1 diabetic mice including upregulation of vitamin D receptor expression, and decreased fibrosis markers such as fibronectin. These effects may contribute to the consistent benefit of vitamin D analog to slow the deterioration in glomerular function and reduce the risk of ESRD in patients with type 1 and 2 diabetes mellitus. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Progression; Ergocalciferols; Fibronectins; Fibrosis; Kidney; Mice, Inbred DBA; Proteinuria; Receptors, Calcitriol; Streptozocin
PubMed: 33294462
DOI: 10.1155/2020/7907605 -
PloS One 2020Conflicting data exists as to whether vitamin D receptor agonists (VDRa) are protective of arterial calcification. Confounding this, is the inherent physiological...
Conflicting data exists as to whether vitamin D receptor agonists (VDRa) are protective of arterial calcification. Confounding this, is the inherent physiological differences between human and animal experimental models and our current fragmented understanding of arterial vitamin D metabolism, their alterations in disease states and responses to VDRa's. Herein, the study aims to address these problems by leveraging frontiers in human arterial organ culture models. Human arteries were collected from a total of 24 patients (healthy controls, n = 12; end-stage CKD, n = 12). Cross-sectional and interventional studies were performed using arterial organ cultures treated with normal and calcifying (containing 5mmol/L CaCl2 and 5mmol/L β-glycerophosphate) medium, ex vivo. To assess the role of VDRa therapy, arteries were treated with either calcitriol or paricalcitol. We found that human arteries express a functionally active vitamin D system, including the VDR, 1α-hydroxylase and 24-hydroxylase (24-OHase) components and these were dysregulated in CKD arteries. VDRa therapy increased VDR expression in healthy arteries (p<0.01) but not in CKD arteries. Arterial 1α-OHase (p<0.05) and 24-OHase mRNA and protein expression were modulated differentially in healthy and CKD arteries by VDRa therapy. VDRa exposure suppressed Runx2 and MMP-9 expression in CKD arteries, however only paricalcitol suppressed MMP-2. VDRa exposure did not modulate arterial calcification in all organ culture models. However, VDRa reduced expression of senescence associated β-galactosidase (SAβG) staining in human aortic-smooth muscle cells under calcifying conditions, in vitro. In conclusion, maladaptation of arterial vitamin D signaling components occurs in CKD. VDRa exposure can exert vasculo-protective effects and seems critical for the regulation of arterial health in CKD.
Topics: Arteries; Calcitriol; Cells, Cultured; Core Binding Factor Alpha 1 Subunit; Cross-Sectional Studies; Ergocalciferols; Female; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Myocytes, Smooth Muscle; Receptors, Calcitriol; Signal Transduction; Vascular Calcification; Vitamin D; Vitamin D3 24-Hydroxylase; beta-Galactosidase
PubMed: 33211721
DOI: 10.1371/journal.pone.0241976 -
BMC Endocrine Disorders Oct 2020Accumulating evidence suggests that low vitamin D status may affect male gonadal structure. This study was undertaken to reveal whether vitamin D-deficient rats have...
BACKGROUND
Accumulating evidence suggests that low vitamin D status may affect male gonadal structure. This study was undertaken to reveal whether vitamin D-deficient rats have demonstrable changes in the quantitative histomorphometric properties of the testis.
METHODS
In the present investigation, adult male Sprague-Dawley rats were divided into four groups and received: group 1) conventional diet; group 2) vitamin D-deficient diet; group 3) vitamin D-deficient diet and paricalcitol and group 4) conventional diet plus paricalcitol. After 3 months, serum levels of vitamin D metabolites, Ca, P, LH, FSH, testosterone, and epididymal sperm quality were evaluated. Moreover, the morphometric characteristics of testis were assessed via stereological methods.
RESULTS
Rats fed a vitamin D-deficient diet (groups 2 and 3) were normocalcemic and had 25-hydroxyvitamin D level below 10 ng/mL. A significant reduction in serum testosterone and comparable gonadotropin levels were seen in vitamin D-deficient groups compared to controls. The concentration, morphology, and motility of sperm cells were profoundly disturbed in animals raised on the vitamin D-deficient diet. There was a significant decline in the population of different germ cells, the volume of interstitial tissue and germinal epithelium in group 2 and 3 rats, which were placed on the vitamin D-deficient diet. No appreciable difference in the estimates of the Leydig or Sertoli cell numbers were observed between groups.
CONCLUSIONS
The depletion of vitamin D stores and induction of moderate grades of vitamin D deficiency by dietary measures led to remarkable impairment of spermatogenesis and microscopic architecture of rat testis. These findings can be attributed, at least in part, to decreased androgen production.
Topics: Animals; Male; Rats; Rats, Sprague-Dawley; Testis; Vitamin D; Vitamin D Deficiency; Vitamins
PubMed: 33121469
DOI: 10.1186/s12902-020-00642-0 -
Cell Metabolism Nov 2020SARS-CoV-2 pneumonitis can quickly strike to incapacitate the lung, leading to severe disease and sometimes death. In this perspective, we suggest that vitamin D...
SARS-CoV-2 pneumonitis can quickly strike to incapacitate the lung, leading to severe disease and sometimes death. In this perspective, we suggest that vitamin D deficiency and the failure to activate the vitamin D receptor (VDR) can aggravate this respiratory syndrome by igniting a wounding response in stellate cells of the lung. The FDA-approved injectable vitamin D analog, paricalcitol, suppresses stellate cell-derived murine hepatic and pancreatic pro-inflammatory and pro-fibrotic changes. Therefore, we suggest a possible parallel program in the pulmonary stellate cells of COVID-19 patients and propose repurposing paricalcitol infusion therapy to restrain the COVID-19 cytokine storm. This proposed therapy could prove important to people of color who have higher COVID-19 mortality rates and lower vitamin D levels.
Topics: Animals; Betacoronavirus; COVID-19; Coronavirus Infections; Cytokines; Drug Repositioning; Ergocalciferols; Humans; Mice; Pandemics; Pneumonia, Viral; Receptors, Calcitriol; SARS-CoV-2; Vitamin D Deficiency; Wound Healing
PubMed: 32941797
DOI: 10.1016/j.cmet.2020.09.007 -
Experimental and Therapeutic Medicine Oct 2020Paricalcitol and cinacalcet have been recommended to reduce parathyroid hormone (PTH) levels for patients with secondary hyperparathyroidism (SHPT) and chronic kidney...
Paricalcitol and cinacalcet have been recommended to reduce parathyroid hormone (PTH) levels for patients with secondary hyperparathyroidism (SHPT) and chronic kidney disease (CKD), and they are able to reduce the risk of hypercalcemia and hyperphosphatemia. However, to date, it has remained uncertain which is the better drug. The aim of the present meta-analysis was to evaluate the effects on PTH, calcium and phosphorus metabolism between the two drugs. The PubMed, the Cochrane Library and Embase databases were searched from inception to June 1, 2019 and eligible studies comparing paricalcitol and cinacalcet for SHPT were included. Data were analysed using Review Manager version 5.3. A total of 7 trials from six articles, comprising 456 patients in the paricalcitol group and 412 patients in the cinacalcet group, were included in the meta-analysis. There were no differences in PTH levels [mean difference (MD): 71.82, 95% CI: -185.20-328.85, P=0.58] and phosphorus levels (standard MD: 0.59, 95% CI: -0.82-2.00, P=0.41). The calcium levels in the paricalcitol group were significantly higher than those in the cinacalcet group (MD: 1.10, 95% CI: 0.92-1.28, P<0.05). In conclusion, paricalcitol and cinacalcet exhibited no difference in their efficacy to control of PTH levels, as they were similarly effective in decreasing the PTH levels. They also had comparable efficacy in the management of phosphorus levels. However, cinacalcet produced a significantly greater reduction in serum calcium levels. More large multicentre randomized controlled trials are necessary to confirm the conclusions of the present analysis.
PubMed: 32855693
DOI: 10.3892/etm.2020.9044 -
Kidney Medicine 2020Mineral and bone disorder in chronic kidney disease (CKD) is associated with progression of coronary artery calcification (CAC). Mineral and bone disorder often is...
RATIONALE & OBJECTIVE
Mineral and bone disorder in chronic kidney disease (CKD) is associated with progression of coronary artery calcification (CAC). Mineral and bone disorder often is treated with calcitriol and other vitamin D receptor activators, including paricalcitol, agents that may have differential effects on calcium, phosphate, and parathyroid hormone levels. Accordingly, we investigated whether these agents have differential effects on CAC progression in patients with CKD.
STUDY DESIGN
Randomized, double-concealed, 48-week clinical trial.
SETTING & PARTICIPANTS
CKD stage 3 or 4 with secondary hyperparathyroidism with CAC score > 0 and no prior treatment with activated vitamin D.
INTERVENTION
Calcitriol versus paricalcitol.
OUTCOMES
The primary outcome was log-transformed CAC change. Secondary outcomes included percent change in CAC volume, valvular calcifications, and bone mineral metabolism markers.
RESULTS
Among 44 individuals randomly assigned, mean age was 65 years and mean estimated glomerular filtration rate was 27 mL/min/1.73 m. Median CAC score was 140 (IQR, 55-277) Agatston units at baseline. There was no significant difference in CAC progression between treatment arms ( = 0.06). After adjustment for baseline CAC score (log), treatment group remains nonsignificant ( = 0.08). Further adjustment for creatinine level and/or CKD stage did not change the association. In secondary analyses adjusting for dose level of activated vitamin D, treatment group was significant ( = 0.01), and when dose level was also included in the model, the coefficient for individuals in the paricalcitol group was significantly associated with CAC progression ( = 0.02). An interaction term between dosing level and CKD stage was significant at the highest dosing level ( = 0.04).
LIMITATIONS
Pilot single-center study.
CONCLUSIONS
In patients with CKD with secondary hyperparathyroidism naive to activated vitamin D therapy, there was no difference in CAC or valvular progression in participants receiving calcitriol compared with paricalcitol during a 48-week period.
FUNDING
Abbvie, Inc.
TRIAL REGISTRATION
NCT00752102.
PubMed: 32775985
DOI: 10.1016/j.xkme.2020.05.009 -
Journal of the American Society of... Sep 2020CKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of...
BACKGROUND
CKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of action are poorly understood.
METHODS
Modulation of the noncanonical NF-B2 pathway and its component TNF receptor-associated factor 3 (TRAF3) by the VDRA paricalcitol was studied in PBMCs from patients with ESKD, cytokine-stimulated cells, and preclinical kidney injury models.
RESULTS
In PBMCs isolated from patients with ESKD, TRAF3 protein levels were lower than in healthy controls. This finding was associated with evidence of noncanonical NF-B2 activation and a proinflammatory state. However, PBMCs from patients with ESKD treated with paricalcitol did not exhibit these features. Experiments in cultured cells confirmed the link between TRAF3 and NF-B2/inflammation. Decreased TRAF3 ubiquitination in K48-linked chains and cIAP1-TRAF3 interaction mediated the mechanisms of paricalcitol action.TRAF3 overexpression by CRISPR/Cas9 technology mimicked VDRA's effects. In a preclinical model of kidney injury, paricalcitol inhibited renal NF-B2 activation and decreased renal inflammation. In VDR knockout mice with renal injury, paricalcitol prevented TRAF3 downregulation and NF-B2-dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol.
CONCLUSIONS
These data suggest the anti-inflammatory actions of paricalcitol depend on TRAF3 modulation and subsequent inhibition of the noncanonical NF-B2 pathway, identifying a novel mechanism for VDRA's effects. Circulating TRAF3 levels could be a biomarker of renal damage associated with the inflammatory state.
Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Cytokine TWEAK; Ergocalciferols; Female; Humans; Kidney Failure, Chronic; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Receptors, Calcitriol; Signal Transduction; TNF Receptor-Associated Factor 3
PubMed: 32631974
DOI: 10.1681/ASN.2019111206 -
International Journal of Emergency... Jun 2020Paricalcitol is known to attenuate ischemic-reperfusion injury of various organs. However, it is not known whether paricalcitol prevents neuronal injury after global...
BACKGROUND
Paricalcitol is known to attenuate ischemic-reperfusion injury of various organs. However, it is not known whether paricalcitol prevents neuronal injury after global cerebral ischemia. The purpose of this study is to investigate the neuroprotective effect of paricalcitol in a rat model of transient global cerebral ischemia.
METHODS
This is a prospective, randomized experimental study. Male Sprague-Dawley rats that survived 10 min of four-vessel occlusion were randomly assigned to two treatment groups: one group was treated with paricalcitol 1 μg/kg IP, and the other was given an equivalent volume of normal saline IP. Drugs were administered at 5 min, 1 day, 2 days, and 3 days after ischemia. Neurologic function was assessed at 2 h, 1 day, 2 days, 3 days, and 4 days after ischemia. We tested motor function 3 days after ischemia using the rotarod test. Also, we tested memory function 4 days after ischemia using the passive avoidance test. We assessed neuronal degeneration in the hippocampus of surviving rats 4 days after ischemia.
RESULTS
Eight rats were allocated to each group. No significant differences were found between the groups in terms of survival rate, motor coordination, or memory function. The neurological function score 2-h post-ischemia was significantly higher in the paricalcitol group (p = 0.04). Neuronal degeneration was significantly less in the paricalcitol group compared with the control group (p = 0.01).
CONCLUSIONS
Paricalcitol significantly attenuated neuronal injury in the hippocampus. Although motor coordination, memory function, and survival rate were not significantly improved by paricalcitol treatment in this study, paricalcitol remains a potential neuroprotective drug after global cerebral ischemia.
PubMed: 32522270
DOI: 10.1186/s12245-020-00289-7 -
PloS One 2020Paricalcitol, a new vitamin D receptor activator (VDRA), is reported to be more effective than other VDRAs in reducing calcium and phosphorus levels in patients... (Comparative Study)
Comparative Study Meta-Analysis
A comparative analysis of the efficacy and safety of paricalcitol versus other vitamin D receptor activators in patients undergoing hemodialysis: A systematic review and meta-analysis of 15 randomized controlled trials.
Paricalcitol, a new vitamin D receptor activator (VDRA), is reported to be more effective than other VDRAs in reducing calcium and phosphorus levels in patients undergoing hemodialysis. However, the efficacy and safety of paricalcitol remain controversial. This analysis compares paricalcitol with other VDRAs in patients undergoing hemodialysis. We searched the Cochrane Library, PubMed, EMBASE, Web of Science, and CNKI up to April 22, 2019. Standardized mean difference (SMD), risk ratio (RR) and 95% confidence interval (CI) values were estimated to compare the outcomes of the groups. Two reviewers extracted data and assessed trial quality independently. All statistical analyses were performed using the standard statistical procedures of RevMan 5.2 and Stata 12.0. Fifteen studies (N = 110,544) were included in this meta-analysis. Of these studies, 11 were randomized controlled trials (RCTs) and 4 were non-randomized studies of interventions (NRSIs). Patients receiving paricalcitol experienced better overall survival (OS) than patients receiving other VDRAs, with a pooled hazard ratio of 0.86 (95% CI 0.80-0.91; P < 0.00001). Intact parathyroid hormone (iPTH) levels were significantly reduced in the paricalcitol group compared to the group receiving other VDRAs, with a pooled SMD of -0.53 (95% CI -0.89- -0.16; P = 0.004). There was a significant increase in serum calcium levels from baseline in the paricalcitol group compared to the other VDRAs group when limiting the analysis to RCTs, with a pooled SMD of 2.14 (95% CI 0.90-3.38; P = 0.0007). Changes in serum calcium levels were significantly lower in the paricalcitol group when the analysis was limited to NRSIs, with a pooled SMD of -0.85 (95% CI -1.34--0.35; P = 0.0008). The NSRI analysis also showed a significant reduction in serum phosphorus levels in the paricalcitol group, with a pooled SMD of -0.57 (95% CI -1.00--0.13; P = 0.01). No significant differences were observed in the incidence of hypercalcemia, hyperphosphatemia, or adverse events. Generally, paricalcitol seems superior to other VDRAs in reducing mortality and iPTH levels in patients undergoing hemodialysis. However, the comparative effectiveness of paricalcitol in reducing serum calcium and phosphorus levels needs further exploration. No significant difference was found in the rate of adverse events.
Topics: Calcium; Disease-Free Survival; Ergocalciferols; Female; Humans; Male; Parathyroid Hormone; Phosphorus; Randomized Controlled Trials as Topic; Receptors, Calcitriol; Renal Dialysis; Survival Rate
PubMed: 32470067
DOI: 10.1371/journal.pone.0233705