RESUMO
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.
Assuntos
Glicemia/metabolismo , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/química , Rim/efeitos dos fármacos , Sobrepeso/sangue , Animais , Benzoatos/farmacologia , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Eicosanoides/metabolismo , Jejum/sangue , Glibureto/farmacologia , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Camundongos , Camundongos Obesos , Tamanho do Órgão/efeitos dos fármacos , Sobrepeso/metabolismo , Sobrepeso/patologia , Sobrepeso/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Solubilidade , Ureia/análogos & derivados , Ureia/farmacologiaRESUMO
This study reports preclinical data showing that the interleukin (IL)-1ß modulation is a new promising target in the pathophysiological context of heart failure. Indeed, in nondiabetic Wistar and diabetic Goto-Kakizaki rats with chronic heart failure induced by myocardial infarction, administration of the IL-1ß antibody gevokizumab improves 'surrogate' markers of survival (i.e., left ventricular remodeling, hemodynamics, and function as well as coronary function). However, whether IL-1ß modulation per se or in combination with standard treatments of heart failure improves long-term outcome in human heart failure remains to be determined.