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Life Science Alliance Jul 2024Defective mitophagy in renal tubular epithelial cells is one of the main drivers of renal fibrosis in diabetic kidney disease. Our gene sequencing data showed the...
Defective mitophagy in renal tubular epithelial cells is one of the main drivers of renal fibrosis in diabetic kidney disease. Our gene sequencing data showed the expression of PINK1 and BNIP3, two key molecules of mitophagy, was decreased in renal tissues of VDR-knockout mice. Herein, streptozotocin (STZ) was used to induce renal interstitial fibrosis in mice. VDR deficiency exacerbated STZ-induced renal impairment and defective mitophagy. Paricalcitol (pari, a VDR agonist) and the tubular epithelial cell-specific overexpression of VDR restored the expression of PINK1 and BNIP3 in the renal cortex and attenuated STZ-induced kidney fibrosis and mitochondrial dysfunction. In HK-2 cells under high glucose conditions, an increased level of α-SMA, COL1, and FN and a decreased expression of PINK1 and BNIP3 with severe mitochondrial damage were observed, and these alterations could be largely reversed by pari treatment. ChIP-qPCR and luciferase reporter assays showed VDR could positively regulate the transcription of and genes. These findings reveal that VDR could restore mitophagy defects and attenuate STZ-induced fibrosis in diabetic mice through regulation of PINK1 and BNIP3.
Topics: Animals; Diabetes Mellitus, Experimental; Mice; Membrane Proteins; Receptors, Calcitriol; Mice, Knockout; Mitophagy; Protein Kinases; Humans; Diabetic Nephropathies; Streptozocin; Male; Mitochondria; Mitochondrial Proteins; Fibrosis; Kidney Tubules; Proto-Oncogene Proteins; Mice, Inbred C57BL; Epithelial Cells; Cell Line; Gene Expression Regulation; Ergocalciferols
PubMed: 38697845
DOI: 10.26508/lsa.202302474 -
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 -
Paricalcitol in hemodialysis patients with secondary hyperparathyroidism and its potential benefits.World Journal of Clinical Cases Nov 2021Secondary hyperparathyroidism (SHPT) is a common complication in patients with end-stage renal disease and it is also common in hemodialysis patients. SHPT can increase... (Clinical Trial)
Clinical Trial
BACKGROUND
Secondary hyperparathyroidism (SHPT) is a common complication in patients with end-stage renal disease and it is also common in hemodialysis patients. SHPT can increase bone fragility and calcification of blood vessels and soft tissues, which greatly increases the risk of death.
AIM
To discuss the outcome, safety and other potential benefits of paricalcitol injection in hemodialysis patients with SHPT.
METHODS
We recruited 40 patients who received hemodialysis at our hospital for chronic renal failure with SHPT between March and December 2019. They received paricalcitol injection for 24 wk (starting dose, 0.06-0.08 μg/kg), three times per week. They were followed up at the baseline (week 0), week 4, week 12 and week 24. The primary outcome indicator was the percentage of patients with a > 30% decrease in intact parathyroid hormone (iPTH) levels at week 24 compared with the baseline. The secondary outcome indicators included percentage decrease in iPTH levels at week 24, standard-reaching rate of iPTH (percentage of patients with iPTH down to 130-585 pg/mL), changes in serum levels of calcium (Ca), phosphate (P), Ca × P product, alkaline phosphatase (ALP), creatinine (Cre), hemoglobin (Hb), and C-reactive protein (CRP), and incidence of adverse events (AEs).
RESULTS
After 24 wk of treatment, iPTH levels decreased significantly (598.88 ± 381.29 pg/mL 888.84 ± 376.88 pg/mL, < 0.05). More than 30% decrease of iPTH was found in 21 of 36 (58.33%) patients. The average decrease in iPTH levels was 32.16 ± 4.33%; the standard-reaching rate of iPTH levels was 66.67% (24/36); and ALP levels decreased significantly compared with the baseline (113.72 ± 41.73 IU/L 133.45 ± 56.86 IU/L) ( = 2.798, < 0.05). There were no significant differences in the serum levels of calcium, Hb, Cre and CRP compared with the baseline ( > 0.05). After 24 wk of treatment, serum P levels decreased compared with the baseline (1.91 ± 0.40 mmol/L 2.16 ± 0.66 mmol/L) ( = 2.830, < 0.05). Ca × P product decreased significantly compared with the baseline (56.38 ± 13.22 mg/dL 63.97 ± 20.30 mg/dL) ( = 2.717, < 0.05). No serious adverse events occurred.
CONCLUSION
Paricalcitol was a safe and effective treatment for hemodialysis patients with SHPT. It decreased serum levels of iPTH, ALP and P and maintained stability of serum Ca levels.
PubMed: 34904087
DOI: 10.12998/wjcc.v9.i33.10172 -
Frontiers in Physiology 2023Our previous study showed that vitamin D (VD)-vitamin D receptor () plays a nephroprotective role in lipopolysaccharide (LPS)-induced acute kidney injury (AKI)....
Our previous study showed that vitamin D (VD)-vitamin D receptor () plays a nephroprotective role in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Recently, glucose metabolism reprogramming was reported to be involved in the pathogenesis of AKI. To investigate the role of VD- in glucose metabolism reprogramming in LPS-induced AKI. We established a model of LPS-induced AKI in knockout (-KO) mice, renal proximal tubular-specific -overexpressing (-OE) mice and wild-type C57BL/6 mice. , human proximal tubular epithelial cells (HK-2 cells), knockout and overexpression HK-2 cell lines were used. Paricalcitol (an active vitamin D analog) or -OE reduced lactate concentration, hexokinase activity and PDHA1 phosphorylation (a key step in inhibiting aerobic oxidation) and simultaneously ameliorated renal inflammation, apoptosis and kidney injury in LPS-induced AKI mice, which were more severe in -KO mice. In experiments, glucose metabolism reprogramming, inflammation and apoptosis induced by LPS were alleviated by treatment with paricalcitol or dichloroacetate (DCA, an inhibitor of p-). Moreover, paricalcitol activated the phosphorylation of -activated protein kinase (), and an inhibitor partially abolished the protective effect of paricalcitol in LPS-treated HK-2 cells. VD- alleviated LPS-induced metabolic reprogramming in the kidneys of AKI mice, which may be attributed to the inactivation of phosphorylation the pathway.
PubMed: 36909229
DOI: 10.3389/fphys.2023.1083643 -
The Chinese Journal of Physiology 2023Acute cardiomyopathy is a significant global health concern and one of the leading causes of death in developed countries. Prior studies have shown an association...
Paricalcitol improved cardiac hypertrophy and fibrosis through upregulation of fibroblast growth factor-23 and downregulation of transforming growth factor-beta in a rat model of isoproterenol-induced cardiomyopathy.
Acute cardiomyopathy is a significant global health concern and one of the leading causes of death in developed countries. Prior studies have shown an association between acute cardiomyopathy and low vitamin D levels. Although paricalcitol, a vitamin D receptor (VDR) activator, has demonstrated clinical benefits in patients with advanced kidney disease, its effect on cardiac remodeling in cardiomyopathy is unknown. This study aimed to investigate the relative effects of paricalcitol on cardiomyopathy in rats. Wistar-Kyoto rats were administered vehicle (sham control group) or isoproterenol to induce cardiomyopathy. Rats administered isoproterenol were subsequently treated with paricalcitol (experimental group) or vehicle (isoproterenol group). Picrosirius red and immunofluorescence staining were used to analyze cardiac fibrosis and hypertrophy. Immunohistochemistry staining was used to confirm the molecular mechanisms involved in isoproterenol-induced cardiomyopathy in rats. Injection of paricalcitol could reduce collagen and transforming growth factor-beta 1 (TGF-β1) levels while activating fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor-23 (FGF23) without the help of Klotho, thereby reducing myocardial hypertrophy and fibrosis. As a VDR activator, paricalcitol reduces isoproterenol-induced cardiac fibrosis and hypertrophy by reducing the expression of TGF-β1 and enhancing the expression of VDR, FGFR1, and FGF23.
Topics: Humans; Rats; Animals; Transforming Growth Factor beta1; Up-Regulation; Isoproterenol; Transforming Growth Factor beta; Down-Regulation; Fibroblast Growth Factor-23; Rats, Inbred WKY; Cardiomyopathies; Cardiomegaly; Fibrosis; Transforming Growth Factors
PubMed: 37929341
DOI: 10.4103/cjop.CJOP-D-23-00048 -
Experimental Biology and Medicine... Jan 2023The vascular endothelium is one of the main targets of oxidative stress which plays an important role in the pathophysiology of vascular damage. Recent studies show that...
The vascular endothelium is one of the main targets of oxidative stress which plays an important role in the pathophysiology of vascular damage. Recent studies show that vitamin D can positively regulate endothelial functions in various chronic diseases and in cases of increased oxidative stress. In our study, we investigated the restorative and protective potentials of paricalcitol which is frequently used in patients with chronic renal failure, a vitamin D analogue, in human umbilical vein endothelial cells (HUVEC) before and after HO-induced oxidative stress. Paricalcitol treatment after the oxidative stress induced by HO increased cell viability in endothelial cells depending on the dose that was used. While paricalcitol (500 nM) decreased caspase-3 activity and mitochondrial membrane potential loss, it increased nitric oxide (NO) production and reduced glutathione (GSH) levels. Paricalcitol treatment before oxidative stress increased cell viability. It increased NO production and mitochondrial membrane potential while significantly reducing caspase-3 activity. While paricalcitol caused a significant inhibition of protein disulfide isomerase (PDI) reductase activity in healthy endothelial cells, it did not cause a significant change on the PDI reductase activity under oxidative stress conditions. Present study showed that paricalcitol has restorative and protective effects on endothelial cells against oxidative injury, but these effects occur at high concentrations of paricalcitol.
Topics: Humans; Hydrogen Peroxide; Caspase 3; Apoptosis; Human Umbilical Vein Endothelial Cells; Oxidative Stress; Ergocalciferols; Nitric Oxide; Oxidoreductases; Reactive Oxygen Species
PubMed: 36373746
DOI: 10.1177/15353702221101615 -
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 -
Nutrients Nov 2023Vitamin D (VitD) and Vitamin D receptor () are suggested to play protective roles in the intestinal barrier in ulcerative colitis (UC). However, the underlying...
Vitamin D (VitD) and Vitamin D receptor () are suggested to play protective roles in the intestinal barrier in ulcerative colitis (UC). However, the underlying mechanisms remain elusive. Evidence demonstrates that Na/H exchanger isoform 8 (NHE8, SLC9A8) is essential in maintaining intestinal homeostasis, regarded as a promising target for UC therapy. Thus, this study aims to investigate the effects of VitD/VDR on NHE8 in intestinal protection. VitD-deficient mice, mice and mice were employed in this study. Colitis mice were established by supplementing DSS-containing water. Caco-2 cells and 3D-enteroids were used for in vitro studies. VDR siRNA (siVDR), VDR over-expression plasmid (pVDR), TNF-α and NF-κb p65 inhibitor QNZ were used for mechanical studies. The expression of interested proteins was detected by multiple techniques. In colitis mice, paricalcitol upregulated NHE8 expression was accompanied by restoring colonic mucosal injury. In VitD-deficient and colitis mice, NHE8 expression was compromised with more serious mucosal damage. Noteworthily, paricalcitol could not prevent intestinal barrier dysfunction and histological destruction in mice. In Caco-2 cells and enteroids, siVDR downregulated NHE8 expression, further promoted TNF-α-induced NHE8 downregulation and stimulated TNF-α-induced NF-κb p65 phosphorylation. Conversely, QNZ blocked TNF-α-induced NHE8 downregulation in the absence or presence of siVDR. Our study indicates depressed NHE8 expression is responsible for VitD-deficient-induced colitis aggravation. These findings provide novel insights into the molecular mechanisms of VitD/VDR in intestine protection in UC.
Topics: Humans; Animals; Mice; Caco-2 Cells; Tumor Necrosis Factor-alpha; NF-kappa B; Colitis; Intestinal Mucosa; Vitamin D; Vitamin D Deficiency; Mice, Inbred C57BL; Dextran Sulfate; Colitis, Ulcerative
PubMed: 38004229
DOI: 10.3390/nu15224834 -
Annals of Palliative Medicine Jan 2022The aim of this retrospective observational study based on real-world data was to evaluate the efficacy and safety profile of paricalcitol in Chinese hemodialysis (HD)... (Observational Study)
Observational Study
BACKGROUND
The aim of this retrospective observational study based on real-world data was to evaluate the efficacy and safety profile of paricalcitol in Chinese hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT) in routine clinical practice.
METHODS
From the Better Life for Future database, a total of 668 Chinese hemodialysis patients from 104 dialysis centers between January 2015 and May 2019 were included in the analysis set. Intact parathyroid hormone (iPTH), total serum calcium (Ca), phosphate (P), dosage of intravenous (IV) paricalcitol (Zemplar®) were analyzed and discussed via retrospective analysis of the database during the treatment.
RESULTS
Patients were divided into five groups according to the duration of follow-up. Median iPTH levels decreased from 1,183 pg/mL at baseline to 676 pg/mL at the final visit, or 30.88% (P<0.0001). A total of 56.14% of patients had a ≥30% decrease and 29.34% of patients had a ≥50% decrease in iPTH level. Serum Ca levels shown significantly increased in the group of Month 12-24 (P=0.0479). Serum phosphate levels remained stable in all follow-up groups. The average dose of paricalcitol was 20±9 µg/week. The total dose of paricalcitol and baseline iPTH were negatively correlated with the decrease in iPTH levels.
CONCLUSIONS
This is the first national retrospective real-world observational study since intravenous paricalcitol is available in China since 2014. This study demonstrates the use of paricalcitol as an effective and well-tolerated treatment for the control of PTH during its use in routine practice.
Topics: Ergocalciferols; Humans; Kidney Failure, Chronic; Renal Dialysis; Retrospective Studies
PubMed: 35144414
DOI: 10.21037/apm-21-3966 -
Pathophysiology : the Official Journal... Nov 2023As the impacts of diabetes-induced reproductive damage are now evident in young people, we are now in urgent need to devise new ways to protect and enhance the...
Combination Therapy with Enalapril and Paricalcitol Ameliorates Streptozotocin Diabetes-Induced Testicular Dysfunction in Rats via Mitigation of Inflammation, Apoptosis, and Oxidative Stress.
BACKGROUND
As the impacts of diabetes-induced reproductive damage are now evident in young people, we are now in urgent need to devise new ways to protect and enhance the reproductive health of diabetic people. The present study aimed to evaluate the protective effects of enalapril (an ACE inhibitor) and paricalcitol (a vitamin D analog), individually or in combination, on streptozotocin (STZ)-diabetes-induced testicular dysfunction in rats and to identify the possible mechanisms for this protection.
MATERIAL AND METHODS
This study was carried out on 50 male Sprague-Dawley rats; 10 normal rats were allocated as a non-diabetic control group. A total of 40 rats developed diabetes after receiving a single dose of STZ; then, the diabetic rats were divided into four groups of equivalent numbers assigned as diabetic control, enalapril-treated, paricalcitol-treated, and combined enalapril-and-paricalcitol-treated groups. The effects of mono and combined therapy with paricalcitol and enalapril on testicular functions, sperm activity, glycemic state oxidative stress, and inflammatory parameters, as well as histopathological examinations, were assessed in comparison with the normal and diabetic control rats.
RESULTS
As a result of diabetes induction, epididymal sperm count, sperm motility, serum levels of testosterone, follicle-stimulating hormone (FSH) as well as luteinizing hormone (LH), and the antioxidant enzyme activities, were significantly decreased, while abnormal sperm (%), insulin resistance, nitric oxide (NO), malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were significantly increased, along with severe distortion of the testicular structure. Interestingly, treatment with paricalcitol and enalapril, either alone or in combination, significantly improved the sperm parameters, increased antioxidant enzyme activities in addition to serum levels of testosterone, FSH, and LH, reduced insulin resistance, IL-6, and TNF-α levels, and finally ameliorated the diabetes-induced testicular oxidative stress and histopathological damage, with somewhat superior effect for paricalcitol monotherapy and combined therapy with both drugs compared to monotherapy with enalapril alone.
CONCLUSIONS
Monotherapy with paricalcitol and its combination therapy with enalapril has a somewhat superior effect in improving diabetes-induced testicular dysfunction (most probably as a result of their hypoglycemic, antioxidant, anti-inflammatory, and anti-apoptotic properties) compared with monotherapy with enalapril alone in male rats, recommending a synergistic impact of both drugs.
PubMed: 38133142
DOI: 10.3390/pathophysiology30040041