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Kidney Week

Abstract: FR-PO103

A Downstream Molecule of 1,25-Dihydroxyvitamin D3, Alpha-1-Acid Glycoprotein, Protects Against Mouse Model of Renal Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Bi, Jing, Kumamoto University, Kumamoto, Japan
  • Watanabe, Hiroshi, School of Pharmacy, Kumamoto University, Kumamoto, Japan
  • Fujimura, Rui, Kumamoto university, Kumamoto-shi, Japan
  • Nishida, Kento, Department of Biopharmaceutics, School of Pharmacy, Kumamoto University, Kumamoto-shi, Japan
  • Nakamura, Ryota, School of Pharmacy, Kumamoto University, Kumamoto, Japan
  • Oshiro, Shun, Kumamoto University, Kumamoto, Japan
  • Imafuku, Tadashi, Kumamoto University, Kumamoto, Japan
  • Miyahisa, Masako, Kumamoto University, Kumamoto, Japan
  • Maruyama, Toru, School of Pharmacy, Kumamoto University, Kumamoto, Japan
Background

Renal fibrosis, the central feature of the progression of chronic kidney disease, is associated with unremitting renal inflammation. 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, has been reported for its anti-renal fibrotic effect in model of unilateral ureteral obstruction (UUO), but its molecular mechanism is still unknown.

Methods

ICR mice (male, 4-week-old) were randomized and anaesthetized before the abdomen was opened, then the left ureter was ligated with 4-0 silk and the abdomen was closed with sutures. 1,25(OH)2D3 was administered i.p. daily from day 0 to day 6 of the UUO treatment. Alpha-1-acid glycoprotein (AGP) was administered i.v. daily from day 1 to day 6 of the UUO treatment. Mice were sacrificed on day 7 after surgery. Phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells or HepG2 cells were treated with 1,25(OH)2D3 or AGP and incubated for 48 hr. LPS were incubated for 48 hr. Real-time PCR, immunofluorescence and Picrosirius Red staining were performed.

Results

Renal fibrosis and inflammation observed in the kidney of the UUO mice were attenuated by the treatment of 1,25(OH)2D3. Interestingly, the plasma protein level of AGP, a downstream molecule of 1,25(OH)2D3, was increased following the administration of 1,25(OH)2D3 to healthy mice. Additionally, the increase of ORM1, an AGP gene, was observed in 1,25(OH)2D3-treated HepG2 cells and THP-1-derived macrophages. To investigate the involvement of AGP, exogenous AGP was administered to the UUO mice, resulting in attenuated renal fibrosis and inflammation. Regarding the mechanism, we found the mRNA expression of CD163, a monocyte/macrophage marker with anti-inflammatory potential, was increased in THP-1-derived macrophages under 1,25(OH)2D3 or AGP stimulus, respectively. Moreover, AGP prevented lipopolysaccharide-induced macrophage activation.

Conclusion

We found for the first time that AGP could be a key molecule in the protective effect of vitamin D against renal fibrosis. AGP may function as an important immune regulator, replacing vitamin D to offer therapeutic strategy for renal inflammation and fibrosis.