Abstract: SA-PO734
1,25-Dihydroxy-Vitamin D3 Regulates M2 Macrophage Polarization via the VDR-PPARγ Signaling Pathway in Lupus Nephritis Mice
Session Information
- CKD: Mechanisms - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Wang, Jia, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
- Zhang, Jiong, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
Background
Lupus nephritis (LN) is one of most serious manifestation of systemic lupus erythematosus (SLE). Recent studies have shown besides autoantibodies and complement activation, macrophage polarization play a major role in the pathogenesis of LN. 1,25-Dihydroxyvitamin D (1,25(OH)2D3) has immunomodulatory activity, and 1,25(OH)2D3 deficiency is correlated with SLE, especially with activity of LN. This study aimed to explore whether 1,25(OH)2D3 modulates macrophage polarization in LN and its underlying mechanism.
Methods
We compared the levels of 1,25(OH)2D3, renal injury (proteinuria, serum urea), and inflammatory cytokines (TNF-α, interleukin (IL)-10) in MRL-Faslpr mice expressing VDR and VDR knockout (KO) MRL-Faslpr mice. Infiltration with M1-like (iNOS+/CD68+), M2-like macrophages (CD163+/CD68+) in renal tissue were detected using immunohistochemical analysis. Peripheral blood monocytes were isolated in MRL-Faslpr mice, and were incubated with or without 1,25(OH)2D3 (10−8 mol/L). M1 and M2 macrophages in vitro were induced by treating cells with 100 U/mL IFNγ + 5 ng/mL LPS or 10 ng/mL IL-4, respectively. In order to explore the underlying mechanism, these cells were treated with VDR siRNA and the PPARγ antagonist. mRNAs expression levels of iNOS, MR and Arg-1 were assessed by RT-PCR.
Results
In vivo, compared with VDR KO MRL-Faslpr mice, more positive for CD68 and iNOS cells were infiltrated in renal tissues in expressing VDR mice, a phenotype suggestive of M1 macrophages. 1,25(OH)2D3 and IL-10 levels were also observed higher than VDR KO MRL-Faslpr mice, whereas TNF-α, proteinuria, serum urea levels were lower. In vitro, pretreatment with 1,25(OH)2D3 significantly inhibited M1 activation, enhancing M2 macrophage activation. Moreover, it upregulated the expression of anti-inflammatory cytokine IL-10 and MR, Arg-1 mRNA but downregulated the expression of iNOS mRNAs. However, cells treated with VDR siRNA and PPARγ antagonist were decreased the tendency toward M2 polarization. Moreover, the expression of PPARγ was decreased when cells treated with VDR siRNA.
Conclusion
The above results demonstrate that 1,25(OH)2D3 promoted M1 phenotype switching to M2 via the VDR-PPARγ pathway in LN. 1,25(OH)2D3 treatment ameliorated LN-associated renal inflammatory injury.
Funding
- Government Support - Non-U.S.