This study addressed the hypothesis that inhibition of the EETs degrading
enzyme soluble
epoxide hydrolase affords renal protection in the early stage of
diabetic nephropathy. The renal effects of the sEH inhibitor
t-AUCB (10mg/l in
drinking water) were compared to those of the sulfonylurea
glibenclamide (80mg/l), both administered for 8 weeks in FVB mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat) and non-treated HFD mice served as controls. Compared with non-treated HFD mice, HFD mice treated with
t-AUCB had a decreased EET degradation, as shown by their higher plasma EETs-to-DHETs ratio, and an increased EET production, as shown by the increase in EETs+DHETs levels, which was associated with induction of CYP450 epoxygenase expression. Both agents similarly reduced fasting glycemia but only
t-AUCB prevented the increase in the urinary albumine-to-
creatinine ratio in HFD mice. Histopathological analysis showed that
t-AUCB reduced renal
inflammation, which was associated with an increased
mRNA expression of the NFκB inhibitor Iκ≡ and related decrease in MCP-1, COX2 and
VCAM-1 expressions. Finally, there was a marginally significant increase in
reactive oxygen species production in HFD mice, together with an enhanced NOX2 expression. Both agents did not modify these parameters but
t-AUCB increased the expression of the
antioxidant enzyme superoxide dismutase 1. These results demonstrate that, independently from its
glucose-lowering effect, sEH inhibition prevents microalbuminuria and renal
inflammation in
overweight hyperglycemic mice, suggesting that this pharmacological strategy could be useful in the management of
diabetic nephropathy.