Role of hemeoxygenase in the reno-protective effects of soluble epoxide hydrolase inhibition in diabetic spontaneously hypertensive rats

We previously showed that inhibition of soluble epoxide hydrolase (sEH) increased epoxyeicosatrienoic acids (EETs) levels and reduced renal injury in diabetic mice and these changes were associated with induction of hemeoxygenase-1 (HO-1). The present study determines whether the inhibition of HO negates the reno-protective effect of sEH inhibition in diabetic spontaneously hypertensive rats (SHR). After six weeks of induction of diabetes with streptozotocin, SHR were divided into the following groups: untreated, treated with the sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), treated with the HO inhibitor, stannous mesoporphyrin (SnMP), and treated with both inhibitors for four more weeks; non diabetic SHR served as a control group. Induction of diabetes significantly increased renal sEH expression and decreased renal EETs/DHETs ratio without affecting HO-1 activity or expression in SHR. Inhibition of sEH with t-AUCB increased renal EETs/DHETs ratio and HO-1 activity in diabetic SHR; however, it did not significantly alter systolic blood pressure. Treatment of diabetic SHR with t-AUCB significantly reduced the elevation in urinary albumin and nephrin excretion whereas co-administration of the HO inhibitor SnMP with t-AUCB prevented these changes. Immunohistochemical analysis revealed elevations in renal fibrosis as evidenced by increased renal TGF-β levels and fibronectin expression in diabetic SHR and these changes were reduc...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research