The farnesoid X receptor agonist EDP‐305 reduces interstitial renal fibrosis in a mouse model of unilateral ureteral obstruction

Abstract

Farnesoid X receptor (FXR) is a nuclear receptor that has emerged as a key regulator in the maintenance of 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). Male C57Bl/6 mice received a UUO on their left kidney. On postoperative d 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 euthanized on postoperative d 12. EDP‐305 dose‐dependently decreased macrophage infiltration as measured by the F4/80 staining area and proinflammatory cytokine gene expression. EDP‐305 also dose‐dependently reduced interstitial fibrosis as assessed by morphometric quantification of the collagen proportional area and kidney hydroxyproline levels. Finally, yes‐associated protein (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 human kidney 2 cells by increasing inhibitory YAP phosphorylation. YAP inhibition may be a novel antifibrotic mechanism of FXR agonism, and EDP‐305 could be used to treat renal fibrosis.—Li, S., Ghoshal, S., Sojoodi, M., Arora, G., Masia, R., Erstad, D. J., Ferriera, D. S., Li, Y., Wang, G., Lanuti, M., Caravan, P., Or, Y. S., Jiang, L.‐J., Tanabe, K. K., Fuchs, B. C. The farnesoid X receptor agonist EDP‐305 reduces interstitial renal fibrosis in a mouse model of unilateral ureteral obstruction. FASEB J. 33, 7103–7112 (2019). http://www.fasebj.org

EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study

“…In vitro studies demonstrated that EDP-305 regulates bile acid and lipid metabolism, and decreases the expression of proinflammatory and fibrogenic genes 3 . EDP-305 potently regulates the expression of FXR target genes in vivo and is hepatoprotective in multiple rodent models of liver injury and NASH [4][5][6] . In Phase 1 studies, EDP-305 was well tolerated in healthy subjects at single doses up to 80 mg and in subjects with or without presumed NAFLD at multiple daily doses up to 20 mg for 14 days 7 .…”

Recent Advances in the Medicinal Chemistry of Farnesoid X Receptor

“…Several pharmaceutical companies and academic laboratories have developed large number of FXR ligands and continue to diversify the chemical arsenal of FXR ligands. − Several compounds including obeticholic acid (OCA), cilofexor (GS-9674), TERN-101 (LY2562175), nidufexor (LMB763), tropifexor (LNJ-452), and EDP-305, are currently in clinical trials for the treatment of NASH, PBC, PSC, and hepatic fibrosis (Table ). − Unfortunately, many compounds have been halted in preclinical or clinical trials due to undesired side effects, including dyslipidemic effects on high density and low density lipoprotein concentrations, pruritis, and increased risk of liver decompensation in cirrhotic PBC patients. − , FXR agonism lowers HDL concentrations by regulating reverse cholesterol transport and, at least in preclinical models, does not exacerbate atherosclerosis . However, the mechanisms for pruritis and liver decompensation are unclear and constitute a significant hurdle for advancing FXR agonists.…”

Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

“…Furthermore, Yap was revealed to mediate mTORC2-induced renal interstitial fibrosis [12]. Increasing evidence indicated that Yap functioned as a pro-fibrotic factor in kidneys, and targeting Yap improved renal interstitial fibrosis [20,37,38,39]. Ruxolitinib treatment inhibited Yap expression in UUO kidneys, further suggesting that Akt/mTOR/Yap is a potential target signaling by Ruxolitinib.…”

“…Ruxolitinib treatment reduced Akt and mTOR phosphorylation ( Figure 7E-F). Recently, yes-associated protein (Yap) was shown as a downstream of mTOR and involved in UUO kidney [12,20]. Indeed, Ruxolitinib treatment inhibited Yap expression ( Figure 7E-F).…”