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

Xiaoliang Zhang,Min Zhou,Yinfeng Guo,Bicheng Liu,Zhixia Song

doi:10.1155/2015/157834

Xiaoliang Zhang, Min Zhou + Show 3 more

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https://doi.org/10.1155/2015/157834

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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.

Highlights

Chronic kidney disease (CKD), especially diabetic nephropathy (DN), is an emerging health problem that poses a growing socioeconomic burden for societies around the world [1,2,3,4,5]
In order to ascertain the optimum glucose concentration and time point, RAW264.7 cells were first stimulated with glucose in dose- (11.1 mM, 20 mM, 25 mM, and 30 mM) and time- (0 h, 6 h, 12 h, 24 h, 36 h, and 48 h) dependent manners, and the activity of inducible nitric oxide synthase was measured
25 mM glucose gave the maximum response, and there was no difference between the control group and mannitol group, which excluded the effect of hyperosmolarity

Summary

Introduction

Chronic kidney disease (CKD), especially diabetic nephropathy (DN), is an emerging health problem that poses a growing socioeconomic burden for societies around the world [1,2,3,4,5]. A common pathologic feature of DN is the presence of inflammatory cells, mostly mononuclear cell infiltration occurring at early stages in the injured kidneys, followed by tubulointerstitial fibrosis at the later stages of disease progression [2,3,4]. Macrophages are pivotal mediators of glomerular and tubulointerstitial inflammation and fibrosis due to their production of proinflammatory and profibrotic cytokines [2, 6, 7]. The severity of renal inflammation and injury was thought to be correlated with the number of infiltrating macrophages [8].

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