Abstract
Renal fibrosis is a critical event in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). Unfortunately, there are few options to target renal fibrosis in order to develop novel anti-fibrotic agents that could prevent CKD progression to ESRD. We evaluated the efficacy of a novel dual-acting molecule, DM509, in preventing renal fibrosis using the unilateral ureteral obstruction (UUO) renal fibrosis mouse model. DM509 acts simultaneously as a farnesoid X receptor agonist (FXRA) and a soluble epoxide hydrolase inhibitor (sEHi). In this study, groups of 8-12 weeks old C57BL/6J male mice went through either UUO or sham surgery (n=6/group). Mice were pre-treated with DM509 (10mg/kg/d) or vehicle administered in drinking water one day prior to the UUO surgery. Sham, vehicle and DM509 treatments continued until day 10 and blood and kidney tissue were collected for biochemical, histological, and gene expression analysis at the end of the treatment protocol. The UUO group exhibited kidney dysfunction with elevated blood urea nitrogen (BUN) compared to the sham group (63±7 vs. 34±6 mg/dL). DM509 treatment prevented renal dysfunction as evident from 36% lower BUN level in the DM509 treated UUO mice compared to UUO mice treated with vehicle. Vehicle treated UUO mice demonstrated renal fibrosis with elevated kidney hydroxyproline content (213±11 vs. 49±9 μg/mg protein) and kidney collagen positive area (13±2% vs. 1.1±0.1%) compared to the sham group. We found that DM509 treatment prevented renal fibrosis and DM509 treated mice had 34-66% lower levels of kidney hydroxyproline and collagen positive renal area compared to vehicle-treated UUO mice. In conclusion, our data provide evidence that the novel dual-acting FXRA and a sEHi, DM509, prevented renal dysfunction and renal fibrosis in UUO mouse model.
Highlights
Renal fibrosis is considered as critical pathophysiological event in the development and progression of chronic kidney disease (CKD)
We recently developed a bifunctional molecule DM509, that concurrently acts as a farnesoid X receptor (FXR) agonist and soluble epoxide hydrolase inhibitor and demonstrated its marked anti-fibrotic action in liver disease models [10]
Similar kidney protective effects are reported for farnesoid receptor agonists in renal fibrosis [15], diabetic nephropathy [21] and renal ischemia reperfusion injury [7]
Summary
Renal fibrosis is considered as critical pathophysiological event in the development and progression of chronic kidney disease (CKD). Inhibitors and angiotensin II receptor blockers are used to reduce proteinuria and slow CKD progression [6]. These renin-angiotensin system drugs have incomplete efficacy in preventing renal fibrosis and CKD progression. We recently developed a bifunctional molecule DM509, that concurrently acts as a farnesoid X receptor (FXR) agonist and soluble epoxide hydrolase inhibitor (sEHi) and demonstrated its marked anti-fibrotic action in liver disease models [10]. Several recent studies demonstrated anti-fibrotic action for FXR agonists in liver and kidney disease models [7, 16, 21]. Considering the promising anti-fibrotic action in liver disease and potential to treat kidney fibrosis, we determined anti-fibrotic action for the novel bifunctional FXR agonist and sEHi, DM509, in a mouse renal fibrosis model
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