Abstract
Renal fibrosis, the characteristic feature of progressive chronic kidney disease, is associated with unremitting renal inflammation. Although it is reported that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, elicits an anti-renal fibrotic effect, its molecular mechanism is still unknown. In this study, renal fibrosis and inflammation observed in the kidney of unilateral ureteral obstruction (UUO) mice were reduced by the treatment of 1,25(OH)2D3. The plasma protein level of alpha-1-acid glycoprotein (AGP), a downstream molecule of 1,25(OH)2D3, was increased following administration of 1,25(OH)2D3. Additionally, increased mRNA expression of ORM1, an AGP gene, was observed in HepG2 cells and THP-1-derived macrophages that treated with 1,25(OH)2D3. To investigate the involvement of AGP, exogenous AGP was administered to UUO mice, resulting in attenuated renal fibrosis and inflammation. We also found the mRNA expression of CD163, a monocyte/macrophage marker with anti-inflammatory potential, was increased in THP-1-derived macrophages under stimulus from 1,25(OH)2D3 or AGP. Moreover, AGP prevented lipopolysaccharide-induced macrophage activation. Thus, AGP could be a key molecule in the protective effect of 1,25(OH)2D3 against renal fibrosis. Taken together, AGP may replace vitamin D to function as an important immune regulator, offering a novel therapeutic strategy for renal inflammation and fibrosis.
Highlights
In patients with CKD, active vitamin D deficiency is associated with a reduction of renal mass[7] and an increased risk of mortality[8]
Our studies on the ureteral obstruction (UUO)-induced renal fibrosis confirmed that (1) acid glycoprotein (AGP) induction was observed following 1,25(OH)2D3 treatment both in vivo and in vitro (2) AGP treatment attenuated renal fibrosis and inflammation in the UUO mice (3) AGP played an anti-inflammatory role in THP-1-derived macrophages with or without LPS stimulation
These results indicated that AGP, a downstream molecule of vitamin D receptor activator (VDRA), could be important in the protective effect of VDRA against renal fibrosis
Summary
In patients with CKD, active vitamin D deficiency is associated with a reduction of renal mass[7] and an increased risk of mortality[8]. Looking into the immunomodulatory effects of VDRA, we focused on alpha-1-acid glycoprotein (AGP) This acute-phase protein, known as orosomucoid, exhibits a variety of activities including anti-inflammation and immune modulation. We demonstrated that AGP inhibited the production of IL-6 and TNF-α and induced CD163, a specific marker that possess anti-inflammatory potential expressed predominantly on monocyte/macrophage, via the TLR4 pathway[19]. AGP may act as a downstream molecule in the anti-renal fibrotic effects of VDRA. To clarify this issue, we examined the anti-fibrotic activity of 1,25(OH)2D3 using a mouse renal fibrosis model. Real-time PCR demonstrated significantly increased mRNA expression of α-SMA (Fig. 1b), TGF-β (Fig. 1c) and Col1a2 (Fig. 1d) in the UUO-treated kidneys compared with the kidney from healthy control mice at day 7. 1,25(OH)2D3 treatment suppressed the increased hydroxyproline content in the obstructed kidney (Supplementary Fig. S1)
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