Unaltered Diabetes Presentation in NOD Mice Lacking the Vitamin D Receptor

Gysemans, Conny; Etten, Evelyne van; Overbergh, Lutgart; Giulietti, Annapaula; Eelen, Guy; Waer, Mark; Verstuyf, Annemieke; Bouillon, Roger; Mathieu, Chantal

doi:10.2337/db07-1095

Cited by 77 publications

(48 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although a previously published study showed increased expression levels of inflammatory markers like MHC-II and CD86 in BMDCs derived from VDR null diabetes-prone NOD mice [13], we did not observed these alterations here in BMDCs from the VDR null model. The VDR molecule is constitutively or after activation expressed in other immune cells as well [4].…”

Section: Discussioncontrasting

confidence: 51%

“…In this regard,a discrepancy in autoimmune disease severity was observed between vitamin D 3 -deficient and VDR null mice although both yield rickets. Vitamin D 3 -deficient mice with a functional VDR develop autoimmunity more rapidly compared to VDR null mice or WT mice [13,14], with a more aggressive and accelerated type of disease [11,12]. In addition, 1a,25(OH) 2 D 3 treatment has been shown to prevent autoimmunity [19].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, vitamin D 3 deficiency during early life increases the incidence and severity of several autoimmune diseases [11,12]. Remarkably, while absence of ligand accelerates disease, lack of the VDR does not show aggravated symptoms [13,14]. Moreover, in the skin VDR ablation causes total body alopecia and dermal cysts while vitamin D 3 -deficiency does not result in a hair cycle/skin phenotype [15].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The phenotype and function of murine bone marrow-derived dendritic cells is not affected by the absence of VDR or its ability to bind 1α,25-dihydroxyvitamin D3

Vanherwegen

Ferreira

Smeets

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

Self Cite

View full text Add to dashboard Cite

The nuclear vitamin D receptor (VDR) is generally recognized as a ligand-dependent transcription factor that mediates the actions of its natural ligand, 1a,25-dihydroxyvitamin D 3 (1a,25(OH) 2 D 3 ) on multiple target genes involved in mineral homeostasis, bone development, as well as immune reactivity. As the VDR is widely distributed in nearly all cells of the body, it implies that the vitamin D endocrine system may regulate many cell types and functions. Experiments in VDR null mice established that the VDR has intrinsically critical roles in skin and keratinocyte biology but not in immune responses. Oppositely, absence of the VDR ligand is linked to susceptibility to autoimmunity, illustrating a potential role for the unliganded VDR in the immune system. This discrepancy stimulated us to further investigate the impact of the VDR on the phenotype and function of myeloid dendritic cells (DCs) generated ex vivo from bone marrow precursors of VDR null (with a truncated VDR) and VDR DAF2 mice (with a mutated C-terminal activation factor 2 domain thus rendering ligand-induced gene transcription impossible). Absent or unliganded VDR did not affect bone marrow-derived myeloid DC generation. DCs obtained from VDR null and VDR DAF2 bone marrow cells had comparable MHC-II, and costimulatory molecule CD86, CD80 and CD40 expression than DCs from wild-type bone marrow cells. Additionally, an unliganded VDR did not affect the cytokine production nor the antigen-specific T cell stimulatory capacity of bone marrowderived DCs. In conclusion, we showed that although clear effects of 1a,25-dihydroxyvitamin D 3 are described on DC generation, absence of VDR or presence of an unliganded VDR does not affect the profile and function of ex vivo generated bone marrow-derived DCs.

show abstract

Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The phenotype and function of murine bone marrow-derived dendritic cells is not affected by the absence of VDR or its ability to bind 1α,25-dihydroxyvitamin D3

Vanherwegen

Ferreira

Smeets

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Peritoneal macrophage cultures. Resident macrophages were isolated by peritoneal lavage from female 8-to 10-wk-old NOD and C57BL/6 mice and purity (>90%) was assessed by flow cytometry (31). Macrophages from each group were preincubated for 1 h with KDACi (100 nM givinostat or 1 μM vorinostat in medium with 0.01% DMSO) and stimulated for different time periods with LPS (100 μg/mL; Sigma).…”

Section: Methodsmentioning

confidence: 99%

Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection

Christensen

Gysemans

Lundh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Type 1 diabetes is due to destruction of pancreatic β-cells. Lysine deacetylase inhibitors (KDACi) protect β-cells from inflammatory destruction in vitro and are promising immunomodulators. Here we demonstrate that the clinically well-tolerated KDACi vorinostat and givinostat revert diabetes in the nonobese diabetic (NOD) mouse model of type 1 diabetes and counteract inflammatory target cell damage by a mechanism of action consistent with transcription factor-rather than global chromatin-hyperacetylation. Weaning NOD mice received low doses of vorinostat and givinostat in their drinking water until 100-120 d of age. Diabetes incidence was reduced by 38% and 45%, respectively, there was a 15% increase in the percentage of islets without infiltration, and pancreatic insulin content increased by 200%. Vorinostat treatment increased the frequency of functional regulatory T-cell subsets and their transcription factors Gata3 and FoxP3 in parallel to a decrease in inflammatory dendritic cell subsets and their cytokines IL-6, IL-12, and TNF-α. KDACi also inhibited LPS-induced Cox-2 expression in peritoneal macrophages from C57BL/6 and NOD mice. In insulin-producing β-cells, givinostat did not upregulate expression of the anti-inflammatory genes Socs1-3 or sirtuin-1 but reduced levels of IL-1β + IFN-γ-induced proinflammatory Il1a, Il1b, Tnfα, Fas, Cxcl2, and reduced cytokine-induced ERK phosphorylation. Further, NF-κB genomic iNos promoter binding was reduced by 50%, and NF-κB-dependent mRNA expression was blocked. These effects were associated with NF-κB subunit p65 hyperacetylation. Taken together, these data provide a rationale for clinical trials of safety and efficacy of KDACi in patients with autoimmune disease such as type 1 diabetes.inflammation | histone deacetylase | posttranslational modification | epigenetics | autoimmunity

show abstract

“…A key renoprotective function of vitamin D is reduction of albuminuria or proteinuria, major risk factors for CKD progression, renal failure, cardiovascular events, and death. This anti-proteinuric effect and slowing the progression of DN is mediated primarily via the RAAS [50][51][52][53]. Wang and his group from the University of Chicago used the 2.5-kb human podocin gene promoter to target Flag-tagged human VDR (hVDR) to podocytes in DBA/2J mice, a genetic background known to be susceptible to diabetic renal injury.…”

Section: Vitamin D/vdrmentioning

confidence: 99%

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Nakhoul¹,

Nakhoul²,

Nakhoul³

2017

J Clin Exp Nephrol

View full text Add to dashboard Cite

Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality worldwide in patients with type 2 diabetes mellitus. The mechanisms behind the pathophysiology of DN are complex and continue to be not fully understood. Both metabolic (hyperglycaemia) and haemodynamic alterations interact synergistically, and have been reported to activate local RAAS resulting in increased angiotensin-2. In spite the early and chronic treatment with converting enzyme inhibitors and angiotensin receptor blocking drugs, the number of patients reaching end stage renal disease and replacement therapy are increasing.Recently different pathways were proposed to be involved in the pathogenesis of diabetic nephropathy, including the autophagy process, Klotho and the selective agonist vitamin D and his receptor. Under hyperglycemic stress especially in podocytes and proximal convolute tubule cells, there is decrease in the protective autophagic process and increase in cellular damage.α-Klotho is a multifunctional protein highly expressed in the kidney. The klotho protein has endogenous anti fibrotic function via antagonism of Wnt/β-catenin signaling, which promotes fibrogenesis, suggesting that loss of Klotho in early stage of diabetic nephropathy may contribute to the progression of DN by accelerated fibrogenesis.The selective vitamin D agonist and his receptor, play a protective pathway in diabetic nephropathy. A key renoprotective function of vitamin D is to reduce albuminuria or proteinuria, major risk factors for CKD progression, renal failure, cardiovascular events, and death. This antiproteinuric effect and the deceleration of DN progression is mediated primarily via the blocking of the renin angiotensin aldosterone system. In this review we will discuss the different new mechanisms involved in diabetic nephropathy and future therapeutic agents like the mTorc1 blocker, Rapamycin, that can upregulate the autophagy process, the new sodium-glucose transport inhibitors and Paricalcitol, the selective active vitamin D.

show abstract

Unaltered Diabetes Presentation in NOD Mice Lacking the Vitamin D Receptor

Cited by 77 publications

References 25 publications

The phenotype and function of murine bone marrow-derived dendritic cells is not affected by the absence of VDR or its ability to bind 1α,25-dihydroxyvitamin D3

The phenotype and function of murine bone marrow-derived dendritic cells is not affected by the absence of VDR or its ability to bind 1α,25-dihydroxyvitamin D3

Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Contact Info

Product

Resources

About