Type 2 diabetes is a highly prevalent disease worldwide and is continually growing. With diabetic complications like kidney damage, novel therapy development is necessary. The therapy can target the arachidonic acid metabolism. In type 2 diabetes, epoxygenase metabolites of arachidonic acid epoxyeicosatrienoic acids (EETs) are decreased while cyclooxygenase (COX-2) metabolites are increased. It has been shown that COX-2 metabolites have been implicated in renal injury. Therefore, if COX-2 is inhibited, renal injury is decreased. In contrast, the decrease in epoxygenase metabolites contributes to renal injury. EETs have functions that are important in kidney protection, and the activity of EETs is able to be enhanced by reducing their metabolism with soluble epoxide hydrolase (sEH). Inhibiting sEH decreases inflammation and renal injury in type 2 diabetic animal models. With this background, a novel dual-acting COX-2/sEH inhibitor PTUPB was developed and its ability to treat diabetic kidney damage investigated. Two groups (n=4) of 16-weeks old type 2 diabetic ZSF1 rats were used. At this age ZSF1 rats were diabetic, hypertensive and had kidney damage. These rats were treated with vehicle or PTUPB (10mg/kg i.p.) for 8 weeks followed by urine collection. Age matched lean ZSF1 rats treated with vehicle were the control. Urine samples were analyzed to determine kidney damage using colorimetric and ELISA assays for protein and albumin. Renal inflammation and oxidative stress were assessed by measuring urinary excretion of monocyte chemoattractant protein-1 (MCP-1) and TBARS, respectively. All data was analyzed using one-way ANOVA followed by post hoc test. After the 8 week treatment period, the vehicle treated ZSF1 obese rats had increased kidney damage evident with proteinurea (382±52 vs 25±6 mg/d, P&lt;0.05) and albuminurea (72±10 vs 1±0.22 mg/d, P&lt;0.05) compared to lean ZSF1 rats. PTUPB treatment reduced proteinurea (159±27 mg/d, P&lt;0.05) and albuminurea (18±6 mg/d, P&lt;0.05) in the obese ZSF1 rats. PTUPB treatment also reduced renal oxidative stress by reducing urinary TBARS excretion (PTUPB = 2±1 vs vehicle 18±4.3 mg/d, P&lt;0.05). However, PTUPB did not affect urinary MCP-1 in the ZSF1 rats (PTUPB= 16±3.3 vs vehicle = 13±3.7 ng/d, P&lt;0.05). The research demonstrates that the COX-2/sEH inhibitor, PTUPB reduces kidney damage, treats kidney damage in type 2 diabetic ZSF1 obese rats, and has potential to develop as a novel therapy for diabetic kidney damage.

Dual COX-2/sEH inhibitor treats kidney damage in type 2 diabetic rats

253rd National Meeting (2017)

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