The inhibition of soluble epoxide hydrolase protects from retinal vasoregression

Background: Retinal vasoregression is a hallmark of diabetic retinopathy. Inflammatory responses, in particular from microglia, are involved in retinal degeneration. Recruitment and activation of microglia are regulated by Notch signaling and lipid metabolic products. Retinal vessel maturation and quiescence as well as mural cell recruitment are also linked to Notch signaling. Recently, a critical role of sEH in regulation of vascular formation and inflammatory biology was described. Moreover, ω-3 polyunsaturated fatty acids (PFA) can attenuate early retinal degeneration. However, the role of sEH in retinal vasoregression remains unclear.

Aim: This study was aimed at investigating the role of sEH inhibition in retinal vasoregression.

Methods: Male homozygote transgenic polycystic kidney disease rats were treated daily with intraperitoneal injection of a sEH specific inhibitor (Sar5399 30 mg/kg) for four weeks. Retinal digestion preparation was used for quantitative morphometry. sEH expression and microglial activation were quantified using cryosection and whole mount immunofluorecent staining, respectively. sEH activity was measured using a mass spectrometer. Inflammatory and immune-related cytokines were measured using real time PCR. Activation of the Notch signaling pathway was analyzed using western blotting.

Results: sEH activity was upregulated in PKD rats (220%, p < 0.05). Retinal vasoregression was prevented by 39.4% (p < 0.01) sEH inhibition. sEH inhibition reduced retinal pericyte loss (19.6%, p < 0.01) and pericyte migration (30%, p < 0.01). sEH inhibition decreased the activation and recruitment of microglia. The inflammatory cytokines were down-regulated. Moreover, Notch signaling pathway was involved in regulation of microglial recruitment.

Conclusion: The inhibition of Müller cell derived-sEH prevents retinal vasoregression through regulating microglial recruitment.