Abstract: TH-PO081

Palovarotene, Selective Retinoic Receptor-γ Agonist, Inhibited Both BMP4 and TGF-β Signaling Pathways in Diabetic Nephropathy

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Fujita, Yui, Tokushima University, Graduate School of Biomedical Sciences, Tokushima, Japan
  • Tominaga, Tatsuya, Tokushima University, Graduate School of Biomedical Sciences, Tokushima, Japan
  • Tamaki, Masanori, Tokushima University, Graduate School of Biomedical Sciences, Tokushima, Japan
  • Murakami, Taichi, Tokushima University, Graduate School of Biomedical Sciences, Tokushima, Japan
  • Kishi, Seiji, Tokushima University, Graduate School of Biomedical Sciences, Tokushima, Japan
  • Nagai, Kojiro, Tokushima University, Graduate School of Biomedical Sciences, Tokushima, Japan
  • Abe, Hideharu, Tokushima University, Graduate School of Biomedical Sciences, Tokushima, Japan
  • Doi, Toshio, Tokushima University, Graduate School of Biomedical Sciences, Tokushima, Japan
Background

We have reported that the BMP4 / Smad1 signaling pathway play a key role for development of diabetic nephropathy (DN). In recent years, retinoic acid receptor agonists have been focused as therapeutic targets for progressive fibrosis. In this study, we examined the effect of palovarotene, selective retinoic acid receptor-γ agonist, on DN.

Methods

12-15 weeks old ICR mice were rendered diabetic by streptozotocin (STZ). Palovarotene was administered 2 times per week intraperitoneally at 60 μg / kg from 4 weeks after STZ injection. Histological analysis was performed at 12 weeks after administration of palovarotene. BMP4 and TGF-βsignaling pathways were analyzed with in vitro mouse mesangial cells to reveal the mechanism of palovarotene treatment.

Results

Diabetic mice showed significant extracellular matrix expansion associated with increased expressions of phosphorylated (p) Smad1 and type 4 collagen (Col4). The administration of palovarotene in DN reduced the expressions of pSmad1 and Col4 as well as mesangial matrix expansion. Phosphorylated Smad2/3 were increased in DN. Palovarotene administration decreased pSmad2/3.
In cultured mesangial cells, the expressions of BMP4, pSmad1 and Col4 were increased by AGE stimulation. Palovarotene suppressed the increased expressions of BMP4 and Col4 under AGE stimulation. In addition, palovarotene decreased pSmad1 and pSmad2/3 signaling under BMP4 or TGF-β treatment.

Conclusion

Palovarotene has regulated the downstream molecules of the BMP type I receptors, and inhibited pSmad1 and reduced expression of Col4 in mesangial cells. The study has unveiled that palovarotene exerts the suppressive effect for both BMP4 and TGF-β signaling pathways. The findings suggest that the chemicals that targeted a retinoic acid receptor are useful as new therapy for DN.