1,25-Dihydroxyvitamin D-3 Promotes High Glucose-Induced M1 Macrophage Switching to M2 via the VDR-PPAR gamma Signaling Pathway

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 D-3 has renoprotective roles that extend beyond the regulation of mineral metabolism, and PPAR gamma, a nuclear receptor, is essential for macrophage polarization. The present study investigates the effect of 1,25-dihydroxyvitamin D-3 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 TNF alpha and IL-12. While 1,25-dihydroxyvitamin D-3 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 D-3 were abolished when the expression of VDR and PPAR gamma was inhibited by VDR siRNA and a PPAR gamma antagonist. In addition, PPAR gamma 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-PPAR gamma pathway.