Kidney Week

Abstract: SA-PO854

The Farnesoid X Receptor (FXR) Agonist EDP-305 Reduces Interstitial Renal Fibrosis in a Mouse Model of Unilateral Ureteral Obstruction

Session Information

• Molecular Mechanisms of CKD - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Li, Shen, Massachusetts General Hospital, Boston, Massachusetts, United States

Shen Li,

• Ghoshal, Sarani, Massachusetts General Hospital, Boston, Massachusetts, United States

Sarani Ghoshal,

• Arora, Gunisha, Massachusetts General Hospital, Boston, Massachusetts, United States

Gunisha Arora,

• Masia, Ricard, Massachusetts General Hospital, Boston, Massachusetts, United States

Ricard Masia,

• Sojoodi, Mozhdeh, Massachusetts General Hospital, Boston, Massachusetts, United States

Mozhdeh Sojoodi,

• Erstad, Derek, Massachusetts General Hospital, Boston, Massachusetts, United States

Derek Erstad,

• Dos santos ferreira, Diego, Massachusetts General Hospital, Boston, Massachusetts, United States

Diego Dos santos ferreira,

• Li, Yang, Enanta Pharmaceuticals, Inc, Watertown, Massachusetts, United States

Yang Li,

• Caravan, Peter, Massachusetts General Hospital, Boston, Massachusetts, United States

Peter Caravan,

• Or, Yat sun, Enanta Pharmaceuticals, Inc, Watertown, Massachusetts, United States

Yat sun Or,

• Jiang, Li-Juan, Enanta Pharmaceuticals, Inc, Watertown, Massachusetts, United States

Li-Juan Jiang,

• Fuchs, Bryan C., Massachusetts General Hospital, Boston, Massachusetts, United States

Bryan C. Fuchs,

Background

Farnesoid X receptor (FXR) is a nuclear receptor that has emerged as a key regulator in the maintenance of bile acid homeostasis. FXR agonists are currently under clinical investigation for the management of various clinical diseases such as primary biliary cholangitis and nonalcoholic steatohepatitis where they have been shown to reduce hepatic steatosis, inflammation, and fibrosis. However, the role of FXR in renal fibrosis remains to be established. Here, we investigate the effects of the FXR agonist EDP-305 in a mouse model of tubulointerstitial fibrosis via unilateral ureteral obstruction (UUO).

Methods

Male C57Bl/6 mice received a UUO on their left kidney. On postoperative day 4, mice received daily treatment by oral gavage with either vehicle control (0.5% methylcellulose) or 10 or 30 mg/kg EDP-305. All animals were sacrificed on postoperative day 12.

Results

EDP-305 dose-dependently decreased macrophage infiltration as measured by the F4/80 staining area with significant differences seen at the higher dose (4.5±0.46 vs. 1.4±0.49, p<0.01) which were associated with reduced pro-inflammatory cytokine gene expression (Il-6 208.3±59.46 vs. 32.53±3.28, p<0.01; Tnf-α 34.2±10.35 vs. 13.41±2.81, p<0.05). EDP-305 also dose-dependently reduced interstitial fibrosis as assessed by morphometric quantification of the collagen proportional area (CPA) and kidney hydroxyproline (HYP) levels with statistically significant differences observed at the higher dose (CPA 6.73±0.94 vs 2.58±0.39, p<0.01; and HYP 1504±140 vs. 1089±54, p<0.05). Finally, Yap activation, a major driver of fibrosis, increased after UUO injury and was diminished by EDP-305 treatment. Consistently, EDP-305 decreased TGF-β1-induced YAP nuclear localization in HK2 cells by increasing inhibitory YAP phosphorylation.

Conclusion

Our results suggest that Yap inhibition may be a novel anti-fibrotic mechanism of FXR agonism and that FXR agonists could be used to treat renal fibrosis in patients with chronic kidney disease.

Funding

• Commercial Support – Enanta Pharmaceuticals