vitamin-d-2 and Acute-Kidney-Injury

Vitamin D/Vitamin D receptor (VDR) has been shown to inhibit the NF-κB-mediated inflammatory effects. Up-regulation of the NLRP3(Recombinant NLR Family, Pyrin Domain Containing Protein 3)/Caspase-1/GSDMD (Gasdermin D) pathway through NF-κb is one of the key mechanisms leading to pyroptosis. This study aims to explore the effects of vitamin D/VDR on the pyroptosis pathway in cisplatin induced acute kidney injury (AKI) models. Our results showed that in wide type mice, renal function loss, tissue injury and cell death induced by cisplatin were alleviated by pretreatment of high-dose paricalcitol(a VDR agonist) accompanied with up-regulated VDR and decreased expression of NLRP3, GSDMD-N, Cleaved-Caspase-1 and mature Interleukin- 1β (features of pyroptosis). While, in VDR knock out mice, cisplatin induced more severer renal injury and further increased pyroptosis related protein than the wild type mice and the effect of paricalcitol were also eliminated. In tubular cell specific VDR-over expressing mice, those renal injury index as well as pyroptosis phenotype were significantly reduced by low-dose paricalcitol pretreatment with upregulated VDR expression compared with WT mice. In vitro data using gain and lose function experiments in Human tubular epithelial cell (HK-2) were consistent with the observation as in vivo work. Our further experiments in both animal and cell culture work has found that the level of IκBα(Inhibitor of NF-κB) were decreased and the nuclear level of NF-κB p65 of renal tubular cells were increased after cisplatin injury while VDR activation by paricalcitol could reverse up-regulation of nuclear NF-κB p65 with reduced cell pyroptosis. These data suggested that vitamin D/VDR could alleviate cisplatin-induced acute renal injury partly by inhibiting NF-κB-mediated NLRP3/Caspase-1/GSDMD pyroptosis.

Topics: Acute Kidney Injury; Animals; Caspase 1; Cisplatin; Ergocalciferols; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Mice; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphate-Binding Proteins; Pyroptosis; Receptors, Calcitriol; Vitamin D

Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently reported to be involved in AKI. Here in this study, we investigated the internal relation between ferroptosis and the protective effect of VDR in cisplatin induced AKI. By using ferroptosis inhibitor ferrostatin-1 and measurement of ferroptotic cell death phenotype in both in vivo and in vitro cisplatin induced AKI model, we observed the decreased blood urea nitrogen, creatinine, and tissue injury by ferrostatin-1, hence validated the essential involvement of ferroptosis in cisplatin induced AKI. VDR agonist paricalcitol could both functionally and histologically attenuate cisplatin induced AKI by decreasing lipid peroxidation (featured phenotype of ferroptosis), biomarker 4-hydroxynonenal (4HNE), and malondialdehyde (MDA), while reversing glutathione peroxidase 4 (GPX4, key regulator of ferroptosis) downregulation. VDR knockout mouse exhibited much more ferroptotic cell death and worsen kidney injury than wild type mice. And VDR deficiency remarkably decreased the expression of GPX4 under cisplatin stress in both in vivo and in vitro, further luciferase reporter gene assay showed that GPX4 were target gene of transcription factor VDR. In addition, in vitro study showed that GPX4 inhibition by siRNA largely abolished the protective effect of paricalcitol against cisplatin induced tubular cell injury. Besides, pretreatment of paricalcitol could also alleviated Erastin (an inducer of ferroptosis) induced cell death in HK-2 cell. These data suggested that ferroptosis plays an important role in cisplatin induced AKI. VDR activation can protect against cisplatin induced renal injury by inhibiting ferroptosis partly via trans-regulation of GPX4.

Topics: Acute Kidney Injury; Aldehydes; Animals; Antineoplastic Agents; Cell Death; Cell Line; Cisplatin; Creatinine; Cyclohexylamines; Ergocalciferols; Ferroptosis; Glutathione Peroxidase; Humans; Lipid Peroxidation; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Scanning Transmission; Mitochondria; Phenylenediamines; Piperazines; Receptors, Calcitriol; RNA, Small Interfering

Topics: Acute Kidney Injury; Animals; Apoptosis; Apoptosis Regulatory Proteins; Disease Models, Animal; Ergocalciferols; Humans; Kidney Tubules, Proximal; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Proto-Oncogene Proteins; RAW 264.7 Cells; Receptors, Calcitriol; Signal Transduction; Tumor Suppressor Proteins

Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). The inflammatory response that drives IRI involves upregulation of matrix metalloproteinases (MMPs), which results in proteolytic degradation of renal microvascular matrix. Evidence suggests a potential protective role of active vitamin D on ischemic injury by downregulating MMPs. In the present study, we aimed to determine the expression and level of MMP-2 and MMP-9 in renal IRI model and the potential beneficial effect of paricalcitol on both level and expression of MMPs and tubular injury caused by IRI.. 20 Wistar albino rats were divided into three groups: sham-operated, ischemia-reperfusion, and paricalcitol-pretreated. IRI model was induced by bilateral clamping of renal arteries for 45 minutes followed by 24 hours of reperfusion. The analysis of serum creatinine and levels of MMPs were performed after 24 hours of IRI. The effects of paricalcitol on the quantity and expression of MMP-2 and MMP-9 in renal tubular epithelial cells were investigated by enzyme-linked immunosorbent assay and immunohistochemistry, respectively. The pathological examinations were performed to score tubular damage by light microscopy.. Creatinine levels decreased in the paricalcitol group, although this was not proven to be significant. Rats in the paricalcitol group showed significant decrease in both level and expression of MMPs and in tubular injury scores as compared to the IRI group.. Paricalcitol may attenuate renal tubular injury caused by IRI by decreasing both level and expression of MMPs. Further studies are required to investigate the interplay between activated vitamin D and MMPs in AKI.
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Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Ergocalciferols; Kidney; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rats; Rats, Wistar; Reperfusion Injury

The pathophysiology of ischemic acute kidney injury (AKI) is thought to include a complex interplay between vascular endothelial cell dysfunction, inflammation, and tubular cell damage. Several lines of evidence suggest a potential anti-inflammatory effect of vitamin D in various kidney injury models. In this study, we investigated the effect of paricalcitol, a synthetic vitamin D analog, on renal inflammation in a mouse model of ischemia/reperfusion (I/R) induced acute kidney injury (AKI).. Paricalcitol was administered via intraperitoneal (IP) injection at 24h before ischemia, and then I/R was performed through bilateral clamping of the renal pedicles. Twenty-four hours after I/R, mice were sacrificed for the evaluation of injury and inflammation. Additionally, an in vitro experiment using HK-2 cells was also performed to examine the direct effect of paricalcitol on tubular cells.. Pre-treatment with paricalcitol attenuated functional deterioration and histological damage in I/R induced AKI, and significantly decreased tissue neutrophil and macrophage infiltration and the levels of chemokines, the pro-inflammatory cytokine interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). It also decreased IR-induced upregulation of Toll-like receptor 4 (TLR4), and nuclear translocation of p65 subunit of NF-κB. Results from the in vitro study showed pre-treatment with paricalcitol suppressed the TNF-α-induced depletion of cytosolic IκB in HK-2 cells.. These results demonstrate that pre-treatment with paricalcitol has a renoprotective effect in ischemic AKI, possibly by suppressing TLR4-NF-κB mediated inflammation.

Topics: Acute Kidney Injury; Animals; Blotting, Western; Cell Line; Chemokine CCL2; Chemokines; Creatine; Ergocalciferols; Humans; I-kappa B Kinase; Inflammation; Interleukin-6; Kidney; Macrophages; Male; Mice; Mice, Inbred C57BL; Neutrophils; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4; Transcription Factor RelA

Despite the developments in modern medicine, acute renal injury is still a challenging and common health problem. It is well known that ischaemia and reperfusion takes place in pathological mechanisms. Efforts to clarify the pathophysiology and interventions to improve outcomes are essential. Our study aimed to investigate whether the prophylactic use of paricalcitol is beneficial in renal ischaemia/reperfusion (I/R) injury.. Twenty-four Wistar albino rats were assigned randomly to four groups. Right nephrectomies were performed at the time of renal arterial clamping. Sham surgery was performed on the rats in group 1. For the rats in group 2, the left renal artery was clamped for 45 minutes. The rats in group 3 received paricalcitol for seven days (0.2μg/kg/day); following this, a right nephrectomy and left renal arterial clamping were not performed. The rats in group 4 received paricalcitol for seven days (0.2μg/kg/day); following this, a right nephrectomy and left renal arterial clamping for 45 minutes were performed. Tissue thiobarbituric acid reactive substances (TBARS), superoxide dismutase, sulfhydryl groups as well as nitric oxide metabolites, serum urea and creatinine levels were measured for all four groups.. In group 4, there were some improvements in terms of TBARS, nitrite, nitrate, superoxide dismutase and creatinine levels. In the histopathological evaluation, paricalcitol therapy improved tubular necrosis and medullar congestion but there was no significant difference in terms of tubular cell swelling, cellular vacuolisation or general damage. Immunohistopathological examination revealed lower scores for vascular endothelial growth factor in the group 4 rats than in group 2.. Paricalcitol therapy improved renal I/R injury in terms of serum and histopathological parameters. These potential beneficial effects need to be further investigated.

Topics: Acute Kidney Injury; Animals; Constriction; Ergocalciferols; Immunohistochemistry; Kidney; Nephrectomy; Nitric Oxide; Oxidoreductases; Random Allocation; Rats; Rats, Wistar; Receptors, Calcitriol; Reperfusion Injury; Thiobarbituric Acid Reactive Substances

The present study was performed to examine whether paricalcitol may prevent the cisplatin-induced kidney injury. Furthermore, potential molecular mechanisms underlying the protective effect of paricalcitol were explored. Male Sprague-Dawley rats were treated with vehicle (n=12), cisplatin (n=12, 6 mg/kg/day, i.p.), or cisplatin+paricalcitol (n=12, 0.2 μg/kg/day, s.c.) for 4 days. In another series of experiment, HK-2 cells were treated with cisplatin (50 μM), with or without paricalcitol (0.2 ng/ml). Paricalcitol counteracted the cisplatin-induced decline in renal function. Paricalcitol also suppressed the expression of TGF-β1, Smad signaling, and the subsequent epithelial-to-mesenchymal process in cisplatin-treated rats. The expression of P-p53 and p21 was increased in cisplatin-induced nephropathy. These changes were completely prevented or significantly attenuated with paricalcitol co-treatment. The expression of p27(kip1) was increased in cisplatin-treated rats, which was, however, further augmented by the paricalcitol co-treatment. In HK-2 cells, cisplatin increased the expression of p-ERK1/2 and P-p38. Cisplatin also increased the expression of fibronectin and CTGF. Cisplatin increased the expression of pro-apoptotic markers. The expression of CDK2 and Cyclin E as well as that of PCNA was increased. These changes were completely prevented or significantly attenuated by the paricalcitol pretreatment. In contrast, cisplatin increased the expression of p27(kip1), which was further augmented by the paricalcitol-pretreatment. These results suggest that paricalcitol may ameliorate cisplatin-induced renal injury by suppressing the fibrotic, apoptotic and proliferative factors. Its underlying mechanisms may include inhibition of TGF-β1, mitogen-activated protein kinase signaling, p53-induced apoptosis, and augmentation of p27(kip1).

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Apoptosis; Atrophy; Bone Density Conservation Agents; Cell Line; Cell Proliferation; Cisplatin; Cyclin-Dependent Kinase Inhibitor p27; Ergocalciferols; Humans; Kidney; Male; MAP Kinase Signaling System; Protective Agents; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1; Tumor Suppressor Protein p53

Recent studies implicate Wnt/β-catenin signaling in podocyte dysfunction. Because vitamin D analogs can inhibit β-catenin in other tissues, we tested whether the vitamin D analog paricalcitol could ameliorate podocyte injury, proteinuria, and renal fibrosis in adriamycin (ADR) nephropathy. Compared with vehicle-treated controls, paricalcitol preserved expression of nephrin, podocin, and WT1; prevented proteinuria; and reduced glomerulosclerotic lesions induced by ADR. Paricalcitol also inhibited expression of proinflammatory cytokines, reduced renal infiltration of monocytes/macrophages, hampered activation of renal myofibroblasts, and suppressed expression of the fibrogenic TGF-β1, CTGF, fibronectin, and types I and III collagen. Selective suppression of renal Wnt4, Wnt7a, Wnt7b, and Wnt10a expression after ADR accompanied these renoprotective effects of paricalcitol. Significant upregulation of β-catenin, predominantly in podocytes and tubular epithelial cells, accompanied renal injury; paricalcitol largely abolished this induction of renal β-catenin and inhibited renal expression of Snail, a downstream effector of Wnt/β-catenin signaling. Administration of paricalcitol also ameliorated established proteinuria. In vitro, paricalcitol induced a physical interaction between the vitamin D receptor and β-catenin in podocytes, which led to suppression of β-catenin-mediated gene transcription. In summary, these findings suggest that paricalcitol prevents podocyte dysfunction, proteinuria, and kidney injury in adriamycin nephropathy by inhibiting Wnt/β-catenin signaling.

Topics: Acute Kidney Injury; Animals; beta Catenin; Disease Models, Animal; Doxorubicin; Ergocalciferols; Glomerular Mesangium; Male; Mice; Mice, Inbred BALB C; Podocytes; Proteinuria; Signal Transduction; Vitamin D; Wnt Proteins

To report a case of hypervitaminosis D resulting in hypercalcemia and acute kidney injury in a 70-year-old female who was prescribed a standard dose of vitamin D but given a toxic dose of vitamin D 50,000 IU (1.25 mg) daily resulting from a dispensing error.. A 70-year-old female in her usual state of health was instructed to begin supplementation with vitamin D 1000 IU daily. Three months later she developed confusion, slurred speech, unstable gait, and increased fatigue. She was hospitalized for hypercalcemia and acute kidney injury secondary to hypervitaminosis D. All vitamin D supplementation was discontinued and 5 months after discharge, the patient's serum calcium and vitamin D concentrations, as well as renal function, had returned to baseline values. Upon review of the patient's records, it was discovered that she had been taking vitamin D 50,000 IU daily.. There is an increased interest in vitamin D, resulting in more health care providers recommending--and patients taking--supplemental vitamin D. Hypervitaminosis D is rarely reported and generally only in the setting of gross excess of vitamin D. This report highlights a case of hypervitaminosis D in the setting of a prescribed standard dose of vitamin D that resulted in toxic ingestion of vitamin D 50,000 IU daily due to a dispensing error. As more and more people use vitamin D supplements, it is important to recognize that, while rare, hypervitaminosis D is a possibility and dosage conversion of vitamin D units can result in errors.. Health care providers and patients should be educated on the advantages and risks associated with vitamin D supplementation and be informed of safety measures to avoid hypervitaminosis D. In addition, health care providers should understand dosage conversion regarding vitamin D and electronic prescribing and dispensing software should be designed to detect such errors.

Topics: Acute Kidney Injury; Aged; Cholecalciferol; Confusion; Drug Dosage Calculations; Ergocalciferols; Female; Fractures, Bone; Humans; Hypercalcemia; Medication Errors; Treatment Outcome

Vitamin Ds have been reported to have diverse effects on cell homeostasis, leading to suggestions that they have therapeutic applications extending beyond their traditional actions on the Ca2+/parathyroid/bone axis. As some of these potential indications carry an inherent risk of acute renal failure (ARF; eg, cancer chemotherapy and organ transplantation), the goal of this study was to assess whether vitamin Ds directly affect renal tubule injury responses. Cultured human proximal tubular (HK-2) cells were exposed to physiological or pharmacological doses of either calcitriol (D3) or a synthetic vitamin D2 analogue (19-nor) for 3 to 48 hours. Their impact on cell integrity (percent lactate dehydrogenase (LDH) release and tetrazolium dye MTT uptake) under basal conditions and during superimposed injuries (ATP depletion/Ca2+ ionophore or iron-mediated oxidant stress) were determined. As vitamin Ds can be anti-proliferative, cell outgrowth ([3H]thymidine uptake and crystal violet staining) was also tested. Finally, the action of D3 on in vivo ARF (glycerol-induced myoglobinuria) and isolated proximal tubule injury responses were assessed. D3 induced a rapid, dose-dependent increase in HK-2 susceptibility to both ATP-depletion/Ca2+-ionophore- and Fe-mediated attack without independently affecting cell integrity or proliferative responses. In contrast, D2 negatively affected only Fe toxicity and only after relatively prolonged exposure (48 hours). D3 dramatically potentiated in vivo ARF (two- to threefold increase in azotemia), suggesting potential in vivo relevance of the above HK-2 cell results. Proximal tubules, isolated from these glycerol-exposed mice, suggested that D3 can worsen tubule injury despite a parodoxic suppression of H2O2 production. In contrast, D3 had a mild negative impact on cellular energetics (depressed ATP/ADP ratios), and it accentuated plasma membrane phospholipid breakdown. The latter was observed in both glycerol-treated and control tubules, suggesting a primary role in the injury- potentiation effect of D3. Vitamins D(s) may directly, and differentially, increase proximal tubule cell susceptibility to superimposed attack. This property should be considered as new uses for these agents are defined.

Topics: Acute Kidney Injury; Adenosine Triphosphate; Animals; Calcitriol; Calcium; Cell Division; Cell Line; Creatine Kinase; Dose-Response Relationship, Drug; Ergocalciferols; Glycerol; Humans; Hydrogen Peroxide; Iron; Kidney Tubules, Proximal; L-Lactate Dehydrogenase; Male; Mice; Phospholipids; Time Factors

Topics: Acute Kidney Injury; Aged; Chilblains; Ergocalciferols; Frostbite; Humans; Hypercalcemia; Male

Plasma levels of 25-OH-D, 1,25-(OH)2-D and 24,25-(OH)2-D in acute renal failure, chronic glomerulonephritis and chronic renal failure were determined by competitive protein binding assay and evaluated for the correlation with the degree of renal impairment and the influence of dialysis, renal transplantation and the administration of vitamin D and 1-alpha-OH-D3. In this study it is revealed that 25-OH-D deficiency could be normalized by the administration of vitamin D2. Plasma levels of 1,25-(OH)2-D are decreased in proportion to the degree of renal impairment and it is clearly depressed in patients, with a Ccr of 30 ml/min or less. Although biosynthesis of 24,25-(OH)2-D is not remarkably depressed, it is necessary to resolve various questions including the methods of measurement in this respect. It is also disclosed in the present study that 1-alpha-OH-D3 is faster in action than vitamin D2 when used to correct 1,25-(OH)2-D3 deficiency.

Topics: Acute Kidney Injury; Creatinine; Dihydroxycholecalciferols; Ergocalciferols; Glomerulonephritis; Humans; Hydroxycholecalciferols; Kidney Failure, Chronic; Kidney Transplantation; Kinetics; Transplantation, Homologous

Topics: Acute Kidney Injury; Adult; Ergocalciferols; Female; Humans; Hypercalcemia; Hypoparathyroidism; Kidney Function Tests; Vitamin D

Topics: Acute Kidney Injury; Administration, Oral; Dihydrotachysterol; Dose-Response Relationship, Drug; Ergocalciferols; Female; Humans; Hydroxylation; Hyperparathyroidism; Middle Aged