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1,25-Dihydroxyvitamin D₃ Promotes High Glucose-Induced M1 Macrophage Switching to M2 via the VDR-PPARγ Signaling Pathway.

Zhang X, Zhou M, Guo Y, Song Z, Liu B - Biomed Res Int (2015)

Bottom Line: However, the above effects of 1,25-dihydroxyvitamin D3 were abolished when the expression of VDR and PPARγ was inhibited by VDR siRNA and a PPARγ antagonist.In addition, PPARγ was also decreased upon treatment with VDR siRNA.The above results demonstrate that active vitamin D promoted M1 phenotype switching to M2 via the VDR-PPARγ pathway.

View Article: PubMed Central - PubMed

Affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210009, China.

ABSTRACT
Macrophages, especially their activation state, are closely related to the progression of diabetic nephropathy. Classically activated macrophages (M1) are proinflammatory effectors, while alternatively activated macrophages (M2) exhibit anti-inflammatory properties. 1,25-Dihydroxyvitamin D3 has renoprotective roles that extend beyond the regulation of mineral metabolism, and PPARγ, a nuclear receptor, is essential for macrophage polarization. The present study investigates the effect of 1,25-dihydroxyvitamin D3 on macrophage activation state and its underlying mechanism in RAW264.7 cells. We find that, under high glucose conditions, RAW264.7 macrophages tend to switch to the M1 phenotype, expressing higher iNOS and proinflammatory cytokines, including TNFα and IL-12. While 1,25-dihydroxyvitamin D3 significantly inhibited M1 activation, it enhanced M2 macrophage activation; namely, it upregulated the expression of MR, Arg-1, and the anti-inflammatory cytokine IL-10 but downregulated the M1 markers. However, the above effects of 1,25-dihydroxyvitamin D3 were abolished when the expression of VDR and PPARγ was inhibited by VDR siRNA and a PPARγ antagonist. In addition, PPARγ was also decreased upon treatment with VDR siRNA. The above results demonstrate that active vitamin D promoted M1 phenotype switching to M2 via the VDR-PPARγ pathway.

No MeSH data available.


Related in: MedlinePlus

The effect of 1,25(OH)2D3 on the expression of VDR and PPARγ. RAW264.7 cells were stimulated with 1,25(OH)2D3 in a dose- (0.1 nM, 1 nM, 10 nM, and 100 nM) dependent manner. After 24 h, the cells were collected for (a) RT-PCR and (b) western blotting analysis. β-actin was used as an internal control. A concentration of 11.1 mM glucose was used as a control. HG: 25 mM glucose. Data are presented as the mean ± SD (n = 3-4 per group). *P < 0.05 versus control; #P < 0.05 versus HG.
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fig6: The effect of 1,25(OH)2D3 on the expression of VDR and PPARγ. RAW264.7 cells were stimulated with 1,25(OH)2D3 in a dose- (0.1 nM, 1 nM, 10 nM, and 100 nM) dependent manner. After 24 h, the cells were collected for (a) RT-PCR and (b) western blotting analysis. β-actin was used as an internal control. A concentration of 11.1 mM glucose was used as a control. HG: 25 mM glucose. Data are presented as the mean ± SD (n = 3-4 per group). *P < 0.05 versus control; #P < 0.05 versus HG.

Mentions: The biological effects of 1,25(OH)2D3 are mediated through a nuclear hormone receptor known as the vitamin D receptor (VDR), and PPARγ has been suggested to partake in regulating macrophage phenotype. Thus, we explored the expression and interaction of the two receptors. In our study, we found that VDR mRNA was increased by vitamin D in a dose-dependent manner. However, the extent was not significant with 10−10 mol/L (1.18 ± 0.12) and 10−9 mol/L (1.23 ± 0.17) vitamin D stimulation when compared with the control (1.07 ± 0.04). In contrast, 10−8 mol/L (1.90 ± 0.41) and 10−7 mol/L (2.67 ± 0.78) vitamin D obviously upregulated the expression of VDR mRNA, not only with the control but also with the high glucose-treated cells. The VDR protein level showed the same trend. Additionally, PPARγ caused an identical effect as VDR (Figure 6).


1,25-Dihydroxyvitamin D₃ Promotes High Glucose-Induced M1 Macrophage Switching to M2 via the VDR-PPARγ Signaling Pathway.

Zhang X, Zhou M, Guo Y, Song Z, Liu B - Biomed Res Int (2015)

The effect of 1,25(OH)2D3 on the expression of VDR and PPARγ. RAW264.7 cells were stimulated with 1,25(OH)2D3 in a dose- (0.1 nM, 1 nM, 10 nM, and 100 nM) dependent manner. After 24 h, the cells were collected for (a) RT-PCR and (b) western blotting analysis. β-actin was used as an internal control. A concentration of 11.1 mM glucose was used as a control. HG: 25 mM glucose. Data are presented as the mean ± SD (n = 3-4 per group). *P < 0.05 versus control; #P < 0.05 versus HG.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig6: The effect of 1,25(OH)2D3 on the expression of VDR and PPARγ. RAW264.7 cells were stimulated with 1,25(OH)2D3 in a dose- (0.1 nM, 1 nM, 10 nM, and 100 nM) dependent manner. After 24 h, the cells were collected for (a) RT-PCR and (b) western blotting analysis. β-actin was used as an internal control. A concentration of 11.1 mM glucose was used as a control. HG: 25 mM glucose. Data are presented as the mean ± SD (n = 3-4 per group). *P < 0.05 versus control; #P < 0.05 versus HG.
Mentions: The biological effects of 1,25(OH)2D3 are mediated through a nuclear hormone receptor known as the vitamin D receptor (VDR), and PPARγ has been suggested to partake in regulating macrophage phenotype. Thus, we explored the expression and interaction of the two receptors. In our study, we found that VDR mRNA was increased by vitamin D in a dose-dependent manner. However, the extent was not significant with 10−10 mol/L (1.18 ± 0.12) and 10−9 mol/L (1.23 ± 0.17) vitamin D stimulation when compared with the control (1.07 ± 0.04). In contrast, 10−8 mol/L (1.90 ± 0.41) and 10−7 mol/L (2.67 ± 0.78) vitamin D obviously upregulated the expression of VDR mRNA, not only with the control but also with the high glucose-treated cells. The VDR protein level showed the same trend. Additionally, PPARγ caused an identical effect as VDR (Figure 6).

Bottom Line: However, the above effects of 1,25-dihydroxyvitamin D3 were abolished when the expression of VDR and PPARγ was inhibited by VDR siRNA and a PPARγ antagonist.In addition, PPARγ was also decreased upon treatment with VDR siRNA.The above results demonstrate that active vitamin D promoted M1 phenotype switching to M2 via the VDR-PPARγ pathway.

View Article: PubMed Central - PubMed

Affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210009, China.

ABSTRACT
Macrophages, especially their activation state, are closely related to the progression of diabetic nephropathy. Classically activated macrophages (M1) are proinflammatory effectors, while alternatively activated macrophages (M2) exhibit anti-inflammatory properties. 1,25-Dihydroxyvitamin D3 has renoprotective roles that extend beyond the regulation of mineral metabolism, and PPARγ, a nuclear receptor, is essential for macrophage polarization. The present study investigates the effect of 1,25-dihydroxyvitamin D3 on macrophage activation state and its underlying mechanism in RAW264.7 cells. We find that, under high glucose conditions, RAW264.7 macrophages tend to switch to the M1 phenotype, expressing higher iNOS and proinflammatory cytokines, including TNFα and IL-12. While 1,25-dihydroxyvitamin D3 significantly inhibited M1 activation, it enhanced M2 macrophage activation; namely, it upregulated the expression of MR, Arg-1, and the anti-inflammatory cytokine IL-10 but downregulated the M1 markers. However, the above effects of 1,25-dihydroxyvitamin D3 were abolished when the expression of VDR and PPARγ was inhibited by VDR siRNA and a PPARγ antagonist. In addition, PPARγ was also decreased upon treatment with VDR siRNA. The above results demonstrate that active vitamin D promoted M1 phenotype switching to M2 via the VDR-PPARγ pathway.

No MeSH data available.


Related in: MedlinePlus