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Redox Biology Apr 2024To investigate the regulatory effect and mechanism of Vitamin D receptor (VDR) on mitochondrial function in renal tubular epithelial cell under diabetic status.
PURPOSE
To investigate the regulatory effect and mechanism of Vitamin D receptor (VDR) on mitochondrial function in renal tubular epithelial cell under diabetic status.
METHODS
The diabetic rats induced by streptozotocin (STZ) and HK-2 cells under high glocose(HG)/transforming growth factor beta (TGF-β) stimulation were used in this study. Calcitriol was administered for 24 weeks. Renal tubulointerstitial injury and some parameters of mitochondrial function including mitophagy, mitochondrial fission, mitochondrial ROS, mitochondrial membrane potential (MMP), mitochondrial ATP, Complex V activity and mitochondria-associated ER membranes (MAMs) integrity were examined. Additionally, paricalcitol, 3-MA (an autophagy inhibitor), VDR over-expression plasmid, VDR siRNA and Mfn2 siRNA were applied in vitro.
RESULTS
The expression of VDR, Pink1, Parkin, Fundc1, LC3II, Atg5, Mfn2, Mfn1 in renal tubular cell of diabetic rats were decreased significantly. Calcitriol treatment reduced the levels of urinary albumin, serum creatinine and attenuated renal tubulointerstitial fibrosis in STZ induced diabetic rats. In addition, VDR agonist relieved mitophagy dysfunction, MAMs integrity, and inhibited mitochondrial fission, mitochondrial ROS. Co-immunoprecipitation analysis demonstrated that VDR interacted directly with Mfn2. Mitochondrial function including mitophagy, mitochondrial membrane potential (MMP), mitochondrial Ca, mitochondrial ATP and Complex V activity were decreased dramatically in HK-2 cells under HG/TGF-β ambience. In vitro pretreatment of HK-2 cells with autophagy inhibitor 3-MA, VDR siRNA or Mfn2 siRNA negated the activating effects of paricalcitol on mitochondrial function. Pricalcitol and VDR over-expression plasmid activated Mfn2 and then partially restored the MAMs integrity. Additionally, VDR restored mitophagy was partially associated with MAMs integrity through Fundc1.
CONCLUSION
Activated VDR could contribute to restore mitophagy through Mfn2-MAMs-Fundc1 pathway in renal tubular cell. VDR could recover mitochondrial ATP, complex V activity and MAMs integrity, inhibit mitochondrial fission and mitochondrial ROS. It indicating that VDR agonists ameliorate renal tubulointerstitial fibrosis in diabetic rats partially via regulation of mitochondrial function.
Topics: Animals; Rats; Adenosine Triphosphate; Calcitriol; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Epithelial Cells; Fibrosis; Mitochondria; Reactive Oxygen Species; Receptors, Calcitriol; RNA, Small Interfering; Transforming Growth Factor beta
PubMed: 38320454
DOI: 10.1016/j.redox.2024.103062 -
Advanced Science (Weinheim,... Mar 2024Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Ferroptosis, a new form of cell death, plays a crucial role in the pathogenesis of DN....
Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Ferroptosis, a new form of cell death, plays a crucial role in the pathogenesis of DN. Renal tubular injury triggered by ferroptosis might be essential in this process. Numerous studies demonstrate that the vitamin D receptor (VDR) exerts beneficial effects by suppressing ferroptosis. However, the underlying mechanism has not been fully elucidated. Thus, they verified the nephroprotective effect of VDR activation and explored the mechanism by which VDR activation suppressed ferroptosis in db/db mice and high glucose-cultured proximal tubular epithelial cells (PTECs). Paricalcitol (PAR) is a VDR agonist that can mitigate kidney injury and prevent renal dysfunction. PAR treatment could inhibit ferroptosis of PTECs through decreasing iron content, increasing glutathione (GSH) levels, reducing malondialdehyde (MDA) generation, decreasing the expression of positive ferroptosis mediator transferrin receptor 1 (TFR-1), and enhancing the expression of negative ferroptosis mediators including ferritin heavy chain (FTH-1), glutathione peroxidase 4 (GPX4), and cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11). Mechanistically, VDR activation upregulated the NFE2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway to suppress ferroptosis in PTECs. These findings suggested that VDR activation inhibited ferroptosis of PTECs in DN via modulating the Nrf2/HO-1 signaling pathway.
Topics: Animals; Mice; Diabetes Mellitus; Diabetic Nephropathies; Epithelial Cells; Ferroptosis; Glutathione; Heme Oxygenase-1; NF-E2-Related Factor 2; Receptors, Calcitriol; Signal Transduction
PubMed: 38145959
DOI: 10.1002/advs.202305563 -
The Journal of Clinical Endocrinology... Oct 2023Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD) affecting mineral and bone metabolism and characterized by excessive parathyroid... (Meta-Analysis)
Meta-Analysis
CONTEXT
Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD) affecting mineral and bone metabolism and characterized by excessive parathyroid hormone (PTH) production and parathyroid hyperplasia.
OBJECTIVE
The objective of this analysis was to compare the efficacy and adverse effects of extended-release calcifediol (ERC) and paricalcitol (PCT) by assessing their effect on the biomarkers PTH, calcium, and phosphate in patients with non-dialysis CKD (ND-CKD).
METHODS
A systematic literature research was performed in PubMed to identify randomized control trials (RCTs). Quality assessment was done with the GRADE method. The effects of ERC vs PCT were compared using random effects in a frequentist setting.
RESULTS
Nine RCTs comprising 1426 patients were included in the analyses. The analyses were performed on 2 overlapping networks, due to nonreporting of outcomes in some of the included studies. No head-to-head trials were identified. No statistically significant differences in PTH reduction were found between PCT and ERC. Treatment with PCT showed statistically significant increases in calcium compared with ERC (0.2 mg/dL increase; 95% CI, -0.37 to -0.05 mg/dL). No differences in effects on phosphate were observed.
CONCLUSION
This network meta-analysis showed that ERC is comparable in lowering PTH levels vs PCT. ERC displayed avoidance of potentially clinically relevant increases in serum calcium, offering an effective and well-tolerated treatment option for the management of SHPT in patients with ND-CKD.
Topics: Humans; Calcifediol; Calcium; Ergocalciferols; Hyperparathyroidism, Secondary; Network Meta-Analysis; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic; Randomized Controlled Trials as Topic
PubMed: 37235771
DOI: 10.1210/clinem/dgad289 -
International Journal of Molecular... Dec 2023Herein, we measured the antidiabetic and nephroprotective effects of the sodium-glucose cotransporter-2 inhibitor (empagliflozin; SGLT2i) and synthetic active vitamin D...
Herein, we measured the antidiabetic and nephroprotective effects of the sodium-glucose cotransporter-2 inhibitor (empagliflozin; SGLT2i) and synthetic active vitamin D (paricalcitol; Pcal) mono- and co-therapy against diabetic nephropathy (DN). Fifty mice were assigned into negative (NC) and positive (PC) control, SGLT2i, Pcal, and SGLT2i+Pcal groups. Following establishment of DN, SGLT2i (5.1 mg/kg/day) and/or Pcal (0.5 µg/kg/day) were used in the designated groups (5 times/week/day). DN was affirmed in the PC group by hyperglycaemia, dyslipidaemia, polyuria, proteinuria, elevated urine protein/creatinine ratio, and abnormal renal biochemical parameters. Renal SREBP-1 lipogenic molecule, adipokines (leptin/resistin), pro-oxidant (MDA/HO), pro-inflammatory (IL1β/IL6/TNF-α), tissue damage (iNOS/TGF-β1/NGAL/KIM-1), and apoptosis (TUNEL/Caspase-3) markers also increased in the PC group. In contrast, renal lipolytic (PPARα/PPARγ), adiponectin, antioxidant (GSH/GPx1/SOD1/CAT), and anti-inflammatory (IL10) molecules decreased in the PC group. Both monotherapies increased insulin levels and mitigated hyperglycaemia, dyslipidaemia, renal and urine biochemical profiles alongside renal lipid regulatory molecules, inflammation, and oxidative stress. While SGLT2i monotherapy showed superior effects to Pcal, their combination demonstrated enhanced remedial actions related to metabolic control alongside renal oxidative stress, inflammation, and apoptosis. In conclusion, SGLT2i was better than Pcal monotherapy against DN, and their combination revealed better nephroprotection, plausibly by enhanced glycaemic control with boosted renal antioxidative and anti-inflammatory mechanisms.
Topics: Mice; Animals; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors; Glycemic Control; Hydrogen Peroxide; Diabetic Nephropathies; Inflammation; Antioxidants; Anti-Inflammatory Agents; Hyperglycemia; Dyslipidemias
PubMed: 38139208
DOI: 10.3390/ijms242417380 -
Clinical Cancer Research : An Official... Dec 2023Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.
PURPOSE
Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.
PATIENTS AND METHODS
We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2). The primary endpoint was safety, and secondary endpoints included overall response rate, progression-free survival (PFS), and overall survival (OS). Correlative objectives aimed to identify molecular predictors of response and alterations in the tumor stroma.
RESULTS
Twenty patients (10 each in DL1 and DL2) enrolled between March 2019 and May 2021. No grade 3/4 adverse events related to paricalcitol were observed. The most common toxicities were nausea, diarrhea and fatigue, which were similar in both cohorts. Three patients discontinued study after one cycle and were not radiographically evaluable. Of the remaining 17 evaluable patients, 2 had partial response and 12 had stable disease. The median PFS for response-evaluable patients in DL1 was 4.14 months, for DL2 was 4.83 months. Intent-to-treat median OS was 6.15 and 6.66 months for DL1 and DL2, respectively. Correlative studies showed increased tumor vascularity in posttreatment samples in patients receiving the higher dose of paricalcitol (DL2).
CONCLUSIONS
Paricalcitol at 7 mcg/kg/week in combination with Nal-iri/ 5-FU/LV is safely tolerated, may increase tumor vascularity and warrants further investigation.
Topics: Humans; Irinotecan; Gemcitabine; Pilot Projects; Fluorouracil; Liposomes; Pancreatic Neoplasms; Ergocalciferols; Antineoplastic Combined Chemotherapy Protocols; Leucovorin
PubMed: 37801295
DOI: 10.1158/1078-0432.CCR-23-1405 -
Acta Endocrinologica (Bucharest,... 2023Different vitamin D analogs might have advantages over calcitriol.
THE EFFECT OF PARICALCITOL AND CALCITRIOL WITH OR WITHOUT CALCIMIMETICS ON PULSE WAVE VELOCITY AND SERUM LEVELS FOR PARATHYROID HORMONE, CALCIUM AND PHOSPHORUS IN MAINTENANCE HEMODIALYSIS PATIENTS.
CONTEXT
Different vitamin D analogs might have advantages over calcitriol.
OBJECTIVE
To evaluate the effects of paricalcitol . calcitriol based vitamin D receptor activators on calcium-phosphate metabolism and pulse wave velocity in hemodialysis patients.
DESIGN
Observational, cross-sectional and 1 year follow-up study.
SUBJECTS AND METHODS
181 hemodialysis patients were enrolled in this study as divided in to 5 groups based on vitamin D therapy. Baseline and 12 month data on blood biochemistry, pulse wave velocity and cumulative dose of treatments were compared in each study group as well as in overall paricalcitol . calcitriol-based treatment groups.
RESULTS
From baseline to 12 month, significant improvement in pulse wave velocity and parathyroid hormone was shown in paricalcitol-based treatment group without a significant change in calcium, phosphate, alkaline phosphatase. A significant increase in pulse wave velocity, serum phosphate levels, calcium x phosphate product and serum alkaline phosphatase levels were noted in calcitriol-based treatment group with no significant change in serum calcium and parathyroid hormone levels.
CONCLUSION
Our findings revealed superiority of paricalcitol than calcitriol based vitamin D receptor activator therapy in terms of serum phosphate levels, CaxP product, dose requirement for vitamin D and the control of pulse wave velocity.
PubMed: 38933256
DOI: 10.4183/aeb.2023.480 -
International Journal of Molecular... Apr 2024Neointimal hyperplasia is the main cause of vascular graft failure in the medium term. Vitamin D receptor activation modulates the biology of vascular smooth muscle...
Neointimal hyperplasia is the main cause of vascular graft failure in the medium term. Vitamin D receptor activation modulates the biology of vascular smooth muscle cells and has been reported to protect from neointimal hyperplasia following endothelial injury. However, the molecular mechanisms are poorly understood. We have now explored the impact of the selective vitamin D receptor activator, paricalcitol, on neointimal hyperplasia, following guidewire-induced endothelial cell injury in rats, and we have assessed the impact of paricalcitol or vehicle on the expression of key cell stress factors. Guidewire-induced endothelial cell injury caused neointimal hyperplasia and luminal stenosis and upregulated the expression of the growth factor growth/differentiation factor-15 (GDF-15), the cytokine receptor CD74, NFκB-inducing kinase (NIK, an upstream regulator of the proinflammatory transcription factor NFκB) and the chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). Immunohistochemistry confirmed the increased expression of the cellular proteins CD74 and NIK. Paricalcitol (administered in doses of 750 ng/kg of body weight, every other day) had a non-significant impact on neointimal hyperplasia and luminal stenosis. However, it significantly decreased GDF-15, CD74, NIK and MCP-1/CCL2 mRNA expression, which in paricalcitol-injured arteries remained within the levels found in control vehicle sham arteries. In conclusion, paricalcitol had a dramatic effect, suppressing the stress response to guidewire-induced endothelial cell injury, despite a limited impact on neointimal hyperplasia and luminal stenosis. This observation identifies novel molecular targets of paricalcitol in the vascular system, whose differential expression cannot be justified as a consequence of improved tissue injury.
Topics: Animals; Hyperplasia; Rats; Ergocalciferols; Male; Chemokine CCL2; Anti-Inflammatory Agents; Neointima; Growth Differentiation Factor 15; Tunica Intima; Antigens, Differentiation, B-Lymphocyte; Endothelial Cells; Histocompatibility Antigens Class II
PubMed: 38732029
DOI: 10.3390/ijms25094814 -
Scientific Reports Jul 2023To investigate the effects and mechanism of Vitamin D receptor (VDR) signaling on arteriovenous fistula (AVF) endothelial cell injury. Venous tissues of AVF stenosis...
To investigate the effects and mechanism of Vitamin D receptor (VDR) signaling on arteriovenous fistula (AVF) endothelial cell injury. Venous tissues of AVF stenosis patients were collected and analyzed, vascular morphology, reactive oxygen species (ROS), and the expression of VDR, P66Shc, fibronectin (FN), collagen-1 (Col-1) were detected. In addition, human umbilical vein endothelial cells (HUVECs) was used in in vitro studies. HUVECs was incubated with transforming growth factor-beta (TGF-β, 50 ng/ml). Aditionally, paricalcitol, VDR overexpression plasmid and Pin1 inhibitor Juglone were used to investigate the regulatory mechanism of VDR in mitochondrial ROS. The parameters of ROS (e.g. MitoSox) and the expression of FN, Col-1 were tested. Moreover, the mitochondrial translocation of P66Shc was analyzed. The expression of VDR was obviously decreased in the venous tissues of AVF stenosis patients. On the contrary, the expression of P66Shc, P-P66Shc, FN, Col-1 and 8-OHdG were increased significantly in the venous tissues of AVF stenosis patients (P < 0.05). In line with this, the level of mitochondrial ROS and the expression of P66Shc, P-P66Shc, FN, Col-1 increased obviously in HUVECs cells under TGF-β condition. Both VDR over-expression plasmid and Pin1 inhibitor Juglone could alleviate TGF-β induced endothelial injury. Mechanistically, VDR overexpression plasmid and Juglone could inhibit the expression of Pin1, and then restrain P66Shc mitochondrial translocation, eventually reduce the level of mitochondrial ROS. Our research indicated that activation of VDR could alleviate venous endothelial cell dysfunction through inhibiting Pin1-mediated mitochondrial translocation of P66Shc and consequently reducing mitochondrial ROS. It suggested that VDR signaling might be an effective target for AVF stenosis treatment.
Topics: Humans; Reactive Oxygen Species; Src Homology 2 Domain-Containing, Transforming Protein 1; Constriction, Pathologic; Human Umbilical Vein Endothelial Cells; Arteriovenous Fistula; Receptors, Calcitriol
PubMed: 37422508
DOI: 10.1038/s41598-023-37510-5 -
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 -
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