Transgenic Mice Overexpressing Vitamin D Receptor (VDR) Show Anti-Inflammatory Effects in Lung Tissues

Inflammation ◽  
2017 ◽  
Vol 40 (6) ◽  
pp. 2012-2019 ◽  
Author(s):  
Masaki Ishii ◽  
Yasuhiro Yamaguchi ◽  
Kyoko Isumi ◽  
Sumito Ogawa ◽  
Masahiro Akishita
Keyword(s):  
Vitamin D ◽  
Transgenic Mice ◽  
Vitamin D Receptor ◽  
Anti Inflammatory

scholarly journals TRAF3 Modulation: Novel Mechanism for the Anti-inflammatory Effects of the Vitamin D Receptor Agonist Paricalcitol in Renal Disease

2020 ◽  
Vol 31 (9) ◽  
pp. 2026-2042 ◽  
Author(s):  
Sandra Rayego-Mateos ◽  
Jose Luis Morgado-Pascual ◽  
José Manuel Valdivielso ◽  
Ana Belén Sanz ◽  
Enrique Bosch-Panadero ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Cultured Cells ◽  
Kidney Injury ◽  
Preclinical Model ◽  
Protein Levels ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Injury Models ◽  
Inflammatory Effect

BackgroundCKD 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.MethodsModulation of the noncanonical NF-κB2 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.ResultsIn PBMCs isolated from patients with ESKD, TRAF3 protein levels were lower than in healthy controls. This finding was associated with evidence of noncanonical NF-κB2 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-κB2/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-κB2 activation and decreased renal inflammation. In VDR knockout mice with renal injury, paricalcitol prevented TRAF3 downregulation and NF-κB2–dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol.ConclusionsThese data suggest the anti-inflammatory actions of paricalcitol depend on TRAF3 modulation and subsequent inhibition of the noncanonical NF-κB2 pathway, identifying a novel mechanism for VDRA’s effects. Circulating TRAF3 levels could be a biomarker of renal damage associated with the inflammatory state.

scholarly journals PTPN2 Downregulation Is Associated with Albuminuria and Vitamin D Receptor Deficiency in Type 2 Diabetes Mellitus

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Li Zheng ◽  
Wei Zhang ◽  
Aimei Li ◽  
Yan Liu ◽  
Bin Yi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Vitamin D ◽  
Type 2 Diabetes Mellitus ◽  
Vitamin D Receptor ◽  
High Glucose ◽  
Inflammatory Factors ◽  
Inflammatory Factor ◽  
Anti Inflammatory

Objective. Inflammation plays a major role in albuminuria in type 2 diabetes mellitus (T2DM). Our previous studies have shown that the expression of vitamin D receptor (VDR) is downregulated in T2DM which is closely associated with the severity of albuminuria. In this study, we investigated the expression of anti-inflammatory cytokine protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in T2DM and explored its relationship to albuminuria and VDR. Methods. 101 T2DM patients were divided into three groups based on urinary albumin-to-creatinine ratio (uACR): normal albuminuria (uACR < 30 mg/g, n=29), microalbuminuria (30 mg/g ≤ uACR < 300 mg/g, n=34), and macroalbuminuria (uACR ≥ 300 mg/g, n=38). Thirty healthy individuals were included as controls. Serum was analyzed for PTPN2 and IL-6 expression, and peripheral blood mononuclear cells (PBMCs) were analyzed for PTPN2 and VDR expression. THP-1 cells were incubated with high glucose and further treated with or without paricalcitol, a vitamin D analog. The levels of PTPN2, VDR, IL-6, TNFα, and MCP-1 were analyzed. In addition, anti-inflammatory activities of PTPN2 were further explored in THP-1 cells stimulated with high glucose after PTPN2 silencing or overexpression. Results. PTPN2 expression was downregulated in T2DM with the lowest level observed in macroalbuminuria patients. PTPN2 level positively correlated with VDR but negatively correlated with uACR and IL-6. When stimulated with high glucose, there was an increase in inflammatory factors and a decrease in PTPN2 expression. Treatment with paricalcitol reversed these effects. However, paricalcitol failed to exert anti-inflammatory effects in the setting of PTPN2 knockdown. Thus, low levels of PTPN2 aggravated glucose-stimulated inflammation, while high levels of PTPN2 reduced it. Conclusion. PTPN2, an anti-inflammatory factor regulated by VDR, was reduced in T2DM CKD stages 1-2. Taken together, our results suggest that therapeutic strategies that enhance PTPN2 may be beneficial for controlling inflammation in T2DM.

Elevated osteoblastic vitamin D receptor reduces calcium deficient bone loss in transgenic mice.

Bone ◽  
2000 ◽  
Vol 27 (4) ◽  
pp. 13
Author(s):  
P.A. Baldock ◽  
G.P. Thomas ◽  
N.A. Sims ◽  
N.K. Henderson ◽  
B. Hollis ◽  
...  
Keyword(s):  
Vitamin D ◽  
Bone Loss ◽  
Transgenic Mice ◽  
Vitamin D Receptor

Vitamin D receptor agonists as anti-inflammatory agents

2007 ◽  
Vol 3 (4) ◽  
pp. 477-489 ◽  
Author(s):  
Luciano Adorini ◽  
Susana Amuchastegui ◽  
Elisa Corsiero ◽  
Gilles Laverny ◽  
Thomas Le Meur ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Receptor Agonists ◽  
Anti Inflammatory

scholarly journals Apolipoprotein L1 Dynamics in Human Parietal Epithelial Cell Molecular Phenotype Kinetics

2018 ◽  
Author(s):  
Vinod Kumar ◽  
Himanshu Vashistha ◽  
Xiqian Lan ◽  
Nirupama Chandel ◽  
Kamesh Ayasolla ◽  
...  
Keyword(s):  
Vitamin D ◽  
Epithelial Cell ◽  
Transgenic Mice ◽  
Vitamin D Receptor ◽  
Receptor Agonist ◽  
Feedback Loop ◽  
Molecular Phenotype ◽  
Parietal Epithelial Cell ◽  
Parietal Epithelial Cells ◽  
Apolipoprotein L1

AbstractHuman Parietal Epithelial cells (PECs) are considered as a source of progenitor cells to sustain podocyte (PD) homeostasis. We hypothesized that the absence of apolipoprotein (APO) L1 favors the PEC phenotype and that induction of APOL1 transitions to PD renewal. During PECs’ transition, APOL1 expression coincided with the expression of PD markers (PEC transition) along with down regulation of miR193a. The induction of APOL1 down regulated miR193a and induced PD markers in PECs/HEKs; whereas, the APOL1-silencing in transited (Tr)-PECs/HepG2s up regulated miR193a expression suggesting a reciprocally linked feedback loop relationship between APOL1 and miR193a. HIV, IFN-y, and vitamin D receptor agonist (VDA) induced APOL1 expression and PEC transition markers but down regulated miR193a in PECs/HEKs. Glomeruli in HIV patients and HIV: APOL1 transgenic mice displayed foci of PECs expressing synaptopodin, a PEC transition marker. Since APOL1 silencing in PECs partially attenuated HIV-, VDA-, and IFN-y-induced PECs transition, this would suggest that APOL1 is an important functional constituent of APOL1-miR193a axis.

scholarly journals P0087TRAF3 MODULATION: A NOVEL MECHANISM OF THE ANTI-INFLAMMATORY EFFECTS OF VITAMIN D RECEPTOR AGONIST PARICALCITOL IN RENAL DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Sandra Rayego-Mateos ◽  
Jose Luis Morgado Pascual ◽  
José M Valdivielso ◽  
Ana Sanz ◽  
Enrique Bosch panadero ◽  
...  
Keyword(s):  
Vitamin D ◽  
Renal Disease ◽  
Vitamin D Receptor ◽  
Renal Damage ◽  
Preclinical Models ◽  
Renal Inflammation ◽  
Protein Levels ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Abstract Background and Aims Tumor necrosis factor receptor-associated factors (TRAFs) are critical signaling adaptors downstream of pro-inflammatory receptors, involved in canonical and non-canonical nuclear factor-κB (NF-κB) activation. Vitamin D receptor agonists (VDRAs) exert beneficial effects in renal disease and possess anti-inflammatory properties, but the underlying mechanism remains unknown. Our aim was to investigate TRAF3 involvement on renal disease and its potential modulation by VDRAs. Method Studies were done in isolated peripheral blood mononuclear cells (PBMCs) from end-stage renal disease (ESRD) on haemodialysis (treated or not with VDRAs) patients, healthy donors or cultured renal cells. Preclinical models of renal damage were: unilateral ureteral obstruction (UUO), acute renal damage induced by Folic acid (FA) administration and TWEAK-induced renal inflammation. The effect of VDRA (paricalcitol) was tested in vitro and in vivo. Results In PBMCs isolated from ESRD, TRAF3 protein levels were downregulated compared to healthy controls, associated to activation of non-canonical NF-κB2 (downregulation of RelB or p52/NF-κB2 protein levels) and altered pro-inflammatory cytokine profile. Interestingly, treatment of those patients with the VDRA paricalcitol restored all the described features. In vitro experiments in PBMCs and tubular epithelial cells exposed to inflammatory stimuli showed that paricalcitol prevented TRAF3 downregulation, NF-κB2 activation and proinflammatory genes upregulation. Moreover, immunoprecipitation studies showed that paricalcitol diminished TRAF3 ubiquitination in the K48-linked chains and CIAP1-TRAF3 interaction. TRAF3 overexpression by CRIPS/cas9 technology mimics VDRAs effects. In preclinical models of renal damage paricalcitol inhibited renal NF-κB2 activation, reducing p52 and RelB nuclear accumulation and transcriptional activity associated to lower renal inflammation. In TWEAK-induced renal injury in VDR knockout mice, paricalcitol prevented TRAF3 downregulation and NF-κB2-dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol. Conclusion The present studies identify TRAF3 downregulation as a key feature promoting inflammation in CKD identifying non-canonical NF-κB activation as a key driver of inflammation in this context. The fact that the VDR is not required for paricalcitol actions suggests novel-signaling pathways involved in the anti-inflammatory effect of paricalcitol. This may allow the design of drugs that restore TRAF3 levels but are devoid of VDR-dependent effects on mineral bone metabolism, which may limit the use of VDRAs as anti-inflammatory agents.

scholarly journals Vitamin D Receptor Gene Polymorphism: An Important Predictor of Arthritis Development

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Maryam Mukhtar ◽  
Nadeem Sheikh ◽  
Saira Kainat Suqaina ◽  
Andleeb Batool ◽  
Naz Fatima ◽  
...  
Keyword(s):  
Vitamin D ◽  
Gene Polymorphism ◽  
Vitamin D Receptor ◽  
Active Form ◽  
Disease Onset ◽  
Serum Vitamin ◽  
Biologically Active ◽  
Vdr Gene ◽  
Vdr Gene Polymorphism ◽  
Anti Inflammatory

Vitamin D is an anti-inflammatory molecule and has a role in prevention of arthritis development. Biologically active form 1, 25(OH)2D3 of vitamin D can only exert its action after binding its definite vitamin D receptor encoded by VDR gene. VDR gene polymorphism leads to dysfunctioning of 1, 25(OH)2D3 ultimately disease onset. The purpose of current study was to evaluate the effect of vitamin D level and VDR gene polymorphism on rheumatoid arthritis and osteoarthritis. Blood samples were collected from case and control after taking written consent. Serum was separated and vitamin D level as determined from each sample by ELISA. DNA was extracted from each blood sample and amplified by using gene specific primers. Genotyping was performed by Sangers sequencing and PCR-RFLP technique. It was found that vitamin D level was not significantly different among patients and controls. The rs10735810, rs1544410, rs7975232, and rs731236 were associated with the onset of arthritis at both allelic and genotypic level (p < 0.01). Nucleotide change on rs10735810 site leads to change of tryptophan with arginine. The frequencies of haplotype CGAT, CGGA, CGGT, CTAA, CTAT, TGAA, TGAT, TGGA, and TTGA were higher in patients and act as risk factors of RA onset, whereas haplotypes CGAT, CGAT, CGGT, CTGA, TGAT, TGGA, TTAA, and TTGA were associated with OA onset. In conclusion, serum vitamin D level may be normal among arthritis patients but polymorphism on VDR gene restricts vitamin D to perform its anti-inflammatory function by altering the 1, 25(OH)2 D3 binding sites.

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