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Kidney Week

Abstract: PO2454

Combined Soluble Epoxide Hydrolase Inhibition and Epoxyeicosatrienoic Acid Administration Attenuates the Renal Fibrogenesis Without Additivity or Synergy

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Noh, Mira, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Jang, Hee-Seong, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Padanilam, Babu J., Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background

Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites with biological effects, including anti-apoptotic, anti-inflammatory, and anti-fibrotic functions. Soluble epoxide hydrolase (sEH)-mediated hydrolysis of EETs to dihydroxyeicosatrienoic acids (DHET) attenuates these effects. Recent studies have demonstrated inhibition of sEH prevents renal tubulointerstitial fibrosis and inflammation in chronic kidney disease (CKD) model. Here, we demonstrated the role and underlying mechanism of EETs in unilateral ureteral obstruction (UUO)-induced renal fibrogenesis.

Methods

Eight-week-old male wild type (Ephx2+/+) and Ephx2−/− mice underwent sham or UUO surgical procedures and were treated with the combination of 11,12- and 14,15-EETs (15 µg/kg/day, respectively) using osmotic pump for 7 days following UUO surgery.

Results

EETs administration abolished tubulointerstitial fibrogenesis, as demonstrated by reduced fibroblast activation and collagen deposition after UUO. Furthermore, inflammatory response was prevented as demonstrated by decreased macrophage infiltration and expression of inflammatory cytokines (TGF-β, IL-1β and IL-6) in EETs-administered UUO kidneys. The genetic inhibition of sEH also mitigated UUO-induced renal inflammation and interstitial fibrogenesis. The combination of EET administration and genetic sEH inhibition also attenuated inflammation and renal interstitial fibrogenesis after UUO, but no additive or synergic effect of combined sEH inhibition and EETs administration.

Conclusion

Taken together, our findings provide that the underlying mechanism of EETs in kidney fibrogenesis during obstructive nephropathy, suggesting EETs as a potential therapeutic target of kidney fibrosis progression.

Funding

  • NIDDK Support