Vitamin D Prevents Podocyte Injury via Regulation of Macrophage M1/M2 Phenotype in Diabetic Nephropathy Rats

Abstract

Increasing evidence suggests the heterogeneity of macrophage phenotype and function ultimately determines the outcome of diabetic nephropathy (DN). This study aimed to investigate the effects of vitamin D on macrophage M1/M2 phenotype and its role in preventing podocyte impairment in streptozotocin-induced DN rats. Calcitriol, a bioactive 1,25-dihydroxyvitamin D3, ameliorated proteinuria and renal damage as well as reversed the decline of both nephrin and podocin, crucial structural proteins in podocytes. DN rats showed increased infiltrating macrophages with M1 phenotype characterized by elevated expression of inducible nitric oxide synthase and TNF-α in glomeruli and interstitium, which were inhibited after calcitriol treatment. Interestingly, calcitriol promoted M2 macrophage activation with enhanced expression of CD163, arginase-1, and mannose receptor at week 18 but not at week 8 or 14. The ratio of CD163 to CD68, considered as the proportion of M2 macrophages, was about 2.9-fold higher at week 18 after calcitriol treatment. Furthermore, the protein expression of inducible nitric oxide synthase, a crucial marker of M1 macrophages, was negatively correlated with the expression of either nephrin or podocin, whereas CD163, indicating M2 macrophages, was positively correlated. In vitro, 1,25-dihydroxyvitamin D3 switched high-glucose-induced M1 macrophages toward an M2 phenotype in either U937-derived macrophages or RAW264.7 cells. Our results suggest that vitamin D not only reduces macrophage infiltration and inhibits M1 macrophage activation but also enhances M2 macrophage phenotype to protect against podocyte injury.

Vitamin D3 Partly Antagonizes Advanced-Glycation Endproducts-Induced NFκB Activation in Mouse Podocytes

“…The findings are principally in agreement with our data because retention of the NFκB subunits in the cytoplasma by prolonged binding to IκB-α subsequently destroys NFκB dimers [28]. Podocytes are apparently an important target of vitamin D3 and the hormone influences structure and function of podoyctes through various molecular mechanism [29,30,31,32]. In addition, activation of the NFκB-signaling pathway plays a major role in podocyte apoptosis [33,34,35], a pivotal feature of DN.…”

Paeoniflorin prevents TLR2/4-mediated inflammation in type 2 diabetic nephropathy

“…In recent studies, increasing evidence demonstrated that the phenotype of the infiltrated macrophage was the major character that ultimately decided the sequelae of DN (27). M1 macrophages promote the inflammatory response and tissue injury, while the M2 macrophages provide the anti-inflammatory and tissue protective effects (28).…”

“…M1 macrophages promote the inflammatory response and tissue injury, while the M2 macrophages provide the anti-inflammatory and tissue protective effects (28). The transformation of M1 phenotype could be initiated by pro-inflammatory cytokines such as IFN-y, and TNF-α, which in turn enhanced the secretion of these pro-inflammatory cytokines (27). In our experiment, iNOS, as the key M1 macrophage marker, was shown to estimate the population of activated macrophages and the severity of inflammation in DN models.…”

1,25-Dihydroxyvitamin D₃ Facilitates M2 Polarization and Upregulates TLR10 Expression on Human Microglial Cells

“…Similar effects of 1,25(OH) 2 D 3 on M1/M2 polarization have recently been reported in studies in murine macrophages. In a rat model of diabetic nephropathy, 1,25(OH) 2 D 3 inhibited M1 macrophage activation, inflammation and renal injury while it enhanced M2 activation [26]. In another study, 1,25(OH) 2 D 3 suppressed high-glucose-induced M1 activation of rat macrophages while it enhanced M2 activation [27].…”