title: 1,25-Dihydroxyvitamin D₃ Promotes High Glucose-Induced M1 Macrophage Switching to M2 via the VDR-PPARγ Signaling Pathway.
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.
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210009, China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210009, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210009, China.
authors.forename: Yinfeng
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210009, China.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Song
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu 210009, China.
authors.forename: Bicheng
authors.initials: B
authors.lastname: Liu
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D047495:PPAR gamma; D018167:Receptors, Calcitriol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D002117:Calcitriol; D005947:Glucose